RNA compositions and methods of use thereof in the treatment of cancer

Abstract

The present disclosure provides RNA polynucleotides (e.g., mRNA polynucleotides) encoding for cytokine polypeptides and / or tumor antigen polypeptides and compositions comprising thereof. Also provided are methods to treat cancer, e.g., a cancer that comprises a cold tumor.

Description

[0001]Attorney Docket No.07917-0454WO1 / UMMS 24-66 RNA COMPOSITIONS AND METHODS OF USE THEREOF IN THE TREATMENT OF CANCER CLAIM OF PRIORITY This application claims the benefit of U.S. Provisional Application Serial No. 63 / 654,486, filed on May 31, 2024. The entire contents of the foregoing are incorporated herein by reference. 5 SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically as an XML file named 07917-0454WO1_SL_ST26.xml. The XML file, created on May 30, 2025, is 45,007 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety. 10 TECHNICAL FIELD The present disclosure provides RNA polynucleotides (e.g., mRNA polynucleotides) encoding for cytokine polypeptides and / or tumor antigen polypeptides and compositions comprising thereof. Also provided are methods to treat cancer, e.g., a cancer that comprises a cold tumor.15BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a median 5-year survival rate of only 13% and is projected to be the second leading cause of cancer-related deaths in the United States by 2030 (1, 2). KRAS mutations are present in >90% of PDAC lesions and drive disease onset and 20 progression by promoting tumor cell growth and survival as well as remodeling the surrounding tumor microenvironment (TME) to mediate immune evasion (8). Surgical resection is the only current option for a cure, however most PDAC patients present with disseminated disease and are not therefore eligible for surgical resection (3). Standard-of-care chemotherapy and radiotherapy regimens have limited efficacy,25in part due to a fibrotic and hypovascular TME that leads to poor drug delivery and uptake (4-7). 1 Attorney Docket No.07917-0454WO1 / UMMS 24-66 SUMMARY Pancreatic ductal adenocarcinoma (PDAC) remains a devastating malignancy, characterized by limited therapeutic options. Most patients are diagnosed with advanced disease, rendering surgery ineffective and limiting the impact of existing 5 therapies. Previous studies from our group have demonstrated that senescence induction via RAS-targeted therapies can activate anti-tumor T cell immunity through the senescence-associated secretory phenotype (SASP), sensitizing tumors to PD-1 blockade. However, the clinical application of these therapies is constrained by toxicity. In the present disclosure, we leveraged mRNA technology to deliver 10 immunostimulatory SASP cytokines (with and without delivery of tumor antigens) directly into the immunosuppressive PDAC tumor microenvironment (TME). Using an in vitro transcription platform, we successfully administered multiple mRNAs simultaneously into PDAC mouse models, inducing local cytokine expression and immune activation. We defined an optimized combination of cytokines that drive 15 innate and adaptive immune responses. Also provided herein are mRNAs encoding tumor antigens which, when integrated with our cytokine mRNA cocktail, markedly increased dendritic cell recruitment and T-cell-mediated tumor clearance. Long-term studies in autochthonous PDAC mouse models showed that combined delivery of cytokine and tumor antigen mRNAs can lead to complete tumor eradication and 20 prolonged survival. Overall, this disclosure demonstrates key immune-modulating cytokines absent in PDAC and establishes a novel mRNA-based immunotherapy platform for clinical translation. Provided herein are methods for treating a cancer, the methods comprising intratumorally administering to a subject in need thereof a composition comprising 25 one or more RNA polynucleotides encoding one or more chemokine polypeptides, one or more cytokine polypeptides, one or more interferon polypeptides, or a combination thereof. In some embodiments, the one or more chemokine polypeptides comprise one or more homeostatic chemokine polypeptides, one or more inflammatory chemokine polypeptides, or a combination thereof. In some 30 embodiments, the one or more homeostatic chemokine polypeptides comprises CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12, CXCL13, or a combination thereof. In some embodiments, the one or more inflammatory chemokine polypeptides comprises CCL2, CCL3, CCL4, CCL5, CCL11, CXCL8, 2 Attorney Docket No.07917-0454WO1 / UMMS 24-66 CXCL10, or a combination thereof. In some embodiments, the one or more cytokine polypeptides comprises IL-1, IL-2, IL-10, IL-12, IL-15, IL-17, IL-18, or a combination thereof. In some embodiments, the one or more interferon polypeptides comprises IFN-α, IFN-β, IFN-γ, or a combination thereof. 5 In some embodiments, the one or more RNA polynucleotides encodes an IL- 12A polypeptide, an IL-12B polypeptide or both, wherein the IL-12A polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO:1, and wherein the IL-12B polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at 10 least 90%, at least 95%, or at least 100% identical to SEQ ID NO:2. In some embodiments, the one or more RNA polynucleotides encodes an IL-15 polypeptide, wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO:3 or SEQ ID NO:4. In some embodiments, the one or more RNA polynucleotides encodes 15 an IL-18 polypeptide, wherein the IL-18 polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO:5 or SEQ ID NO:6. In some embodiments, the one or more RNA polynucleotides encodes a CCL5 polypeptide, wherein the CCL5 polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at 20 least 95%, or at least 100% identical to SEQ ID NO:7. In some embodiments, the one or more RNA polynucleotides encodes a CXCL10 polypeptide, wherein the CXCL10 polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO:8. In some embodiments, the one or more RNA polynucleotides encodes an IFN-β polypeptide, 25 wherein the IFN-β polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO:9. In some embodiments, the one or more RNA polynucleotides encodes an IL- 12 polypeptide, an IL-18 polypeptide, a CXCL10 polypeptide, and an IFN-β polypeptide. In some embodiments, the one or more RNA polynucleotides encodes 30 an IL-12 polypeptide, an IL-18 polypeptide, a CCL5 polypeptide, a CXCL10 polypeptide, and an IFN-β polypeptide. In some embodiments, the one or more RNA polynucleotides encodes an IL-12 polypeptide, an IL-15 polypeptide, an IL-18 polypeptide, a CXCL10 polypeptide, and an IFN-β polypeptide. In some 3 Attorney Docket No.07917-0454WO1 / UMMS 24-66 embodiments, the one or more RNA polynucleotides encodes an IL-12 polypeptide, an IL-15 polypeptide, a CCL5 polypeptide, a CXCL10 polypeptide, and an IFN-β polypeptide. In some embodiments, the one or more RNA polynucleotides encodes an IL-12 polypeptide, an IL-15 polypeptide, an IL-18 polypeptide, a CCL5 5 polypeptide, a CXCL10 polypeptide, and an IFN-β polypeptide. In some embodiments, the one or more RNA polynucleotides further encodes a tumor-specific antigen. In some embodiments, the composition further comprises an immunotherapy. In some embodiments, the administration occurs one or more times. In some 10 embodiments, the administration occurs once daily. In some embodiments, the administration occurs once every three days. In some embodiments, a tumor in the subject has increased immune cell infiltration compared to a tumor in an untreated subject. In some embodiments, a tumor in the subject has increased immune cell activation compared to a tumor in an 15 untreated subject. In some embodiments, a tumor in the subject has increased necrosis compared to a tumor in an untreated subject. In some embodiments, the subject has a survival rate that is increased compared to an untreated subject. In some embodiments, the subject is human. In some embodiments, the cancer is ovarian cancer, breast cancer, endometrial 20 cancer, bladder cancer, esophageal cancer, oral squamous cell carcinoma, brain cancer, prostate cancer, pancreatic cancer, cervical cancer, skin cancer, lung cancer, gastric cancer, or renal cell carcinoma. In some embodiments, the pancreatic cancer comprises exocrine pancreatic cancer, neuroendocrine pancreatic cancer, or a combination thereof. In some embodiments, the pancreatic cancer comprises 25 pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, adenosquamous carcinoma, colloid carcinoma, pancreatic neuroendocrine tumors (NETs), or a combination thereof. In some embodiments, the one or more RNA polynucleotides comprise at least one modification. In some embodiments, the one or more RNA polynucleotides 30 comprises one or more messenger RNA (mRNA) polynucleotides. Also provided herein are compositions comprising one or more RNA polynucleotides encoding one or more chemokine polypeptides, one or more cytokine polypeptides, one or more interferon polypeptides, or a combination thereof, and a 4 Attorney Docket No.07917-0454WO1 / UMMS 24-66 pharmaceutically acceptable carrier. In some embodiments, the one or more chemokine polypeptides comprise one or more homeostatic chemokine polypeptides, one or more inflammatory chemokine polypeptides, or a combination thereof. In some embodiments, the one or more homeostatic chemokine polypeptides comprises 5 CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12, CXCL13, or a combination thereof. In some embodiments, the one or more inflammatory chemokine polypeptides comprises CCL2, CCL3, CCL4, CCL5, CCL11, CXCL8, CXCL10, or a combination thereof. In some embodiments, the one or more cytokine polypeptides comprises IL-1, IL-2, IL-10, IL-12, IL-15, IL-17, IL-18, or a 10 combination thereof. In some embodiments, the one or more interferon polypeptides comprises IFN-α, IFN-β, IFN-γ, or a combination thereof. In some embodiments, the one or more RNA polynucleotides encodes an IL- 12A polypeptide, an IL-12B polypeptide or both, wherein the IL-12A polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at 15 least 95%, or at least 100% identical to SEQ ID NO:1, and wherein the IL-12B polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO:2. In some embodiments, the one or more RNA polynucleotides encodes an IL-15 polypeptide, wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 70%, 20 at least 80%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO:3 or SEQ ID NO:4. In some embodiments, the one or more RNA polynucleotides encodes an IL-18 polypeptide, wherein the IL-18 polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO:5 or SEQ ID NO:6. In some embodiments, the one or more 25 RNA polynucleotides encodes a CCL5 polypeptide, wherein the CCL5 polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO:7. In some embodiments, the one or more RNA polynucleotides encodes a CXCL10 polypeptide, wherein the CXCL10 polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at 30 least 90%, at least 95%, or at least 100% identical to SEQ ID NO:8. In some embodiments, the one or more RNA polynucleotides encodes an IFN-β polypeptide, wherein the IFN-β polypeptide comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO:9. 5 Attorney Docket No.07917-0454WO1 / UMMS 24-66 In some embodiments, the one or more RNA polynucleotides encodes an IL- 12 polypeptide, an IL-18 polypeptide, a CXCL10 polypeptide, and an IFN-β polypeptide. In some embodiments, the one or more RNA polynucleotides encodes an IL-12 polypeptide, an IL-18 polypeptide, a CCL5 polypeptide, a CXCL10 5 polypeptide, and an IFN-β polypeptide. In some embodiments, the one or more RNA polynucleotides encodes an IL-12 polypeptide, an IL-15 polypeptide, an IL-18 polypeptide, a CXCL10 polypeptide, and an IFN-β polypeptide. In some embodiments, the one or more RNA polynucleotides encodes an IL-12 polypeptide, an IL-15 polypeptide, a CCL5 polypeptide, a CXCL10 polypeptide, and an IFN-β 10 polypeptide. In some embodiments, the one or more RNA polynucleotides encodes an IL-12 polypeptide, an IL-15 polypeptide, an IL-18 polypeptide, a CCL5 polypeptide, a CXCL10 polypeptide, and an IFN-β polypeptide. In some embodiments, the composition optionally does not include the one or more RNA polynucleotides that encode an IL-15 polypeptide. In some embodiments, 15 the composition further comprises an immunotherapy. In some embodiments, the one or more RNA polynucleotides comprises one or more messenger RNA (mRNA) polynucleotides. Also provided herein are compositions comprising at least one RNA polynucleotide, wherein the at least one RNA polynucleotide encodes a cytokine 20 polypeptide selected from the group consisting of interleukin 12 (IL-12), interleukin 15 (IL-15), interleukin 18 (IL-18), interferon beta 1 (IFNB1), C-X-C motif chemokine ligand 10 (CXCL10), and C-C motif chemokine ligand 5 (CCL5). In some embodiments, the composition comprises five RNA polynucleotides that encode for the cytokine polypeptides IL-12, IL-18, IFNB1, CXCL10, and CCL5. In some 25 embodiments, the composition comprises six RNA polynucleotides that encode for the cytokine polypeptides IL-12, IL-15, IL-18, IFNB1, CXCL10, and CCL5. In some embodiments, the composition comprises at least one RNA polynucleotide that encodes an IL-18 polypeptide, at least one RNA polynucleotide that encodes a CCL5 polypeptide, and at least one RNA polynucleotide that encodes a cytokine polypeptide 30 selected from the group consisting of IL-12, IL-15, IFNB1, and CXCL10. In some embodiments, the composition comprises at least one RNA polynucleotide that encodes an IL-12 polypeptide, at least one RNA polynucleotide that encodes an IL-18 polypeptide, at least one RNA polynucleotide that encodes an IFNB1 polypeptide, at 6 Attorney Docket No.07917-0454WO1 / UMMS 24-66 least one RNA polynucleotide that encodes a CXCL10 polypeptide, and at least one RNA polynucleotide that encodes a cytokine polypeptide selected from the group consisting of IL-15 and CCL5. In some embodiments, compositions comprising at least one RNA polynucleotide optionally do not comprise an RNA polynucleotide that 5 encodes an IL-15 polypeptide. In some embodiments, compositions comprising at least one RNA polynucleotide optionally comprise at least one RNA polynucleotide that encodes an IL-12 polypeptide in addition to at least one RNA polynucleotide that encodes a cytokine polypeptide other than an IL-12 polypeptide. In some embodiments, the at least one RNA polynucleotide encodes an IL- 10 12A polypeptide, an IL-12B polypeptide or both. In some embodiments, the at least one RNA polynucleotide encodes an IL-12A polypeptide wherein the IL-12A polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 1. In some embodiments, the at least one RNA polynucleotide encodes an IL- 12A polypeptide wherein the IL-12A polypeptide comprises an amino acid sequence 15 that is identical to SEQ ID NO: 1. In some embodiments, the at least one RNA polynucleotide encodes an IL-12B polypeptide wherein the IL-12B polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 2. In some embodiments, the at least one RNA polynucleotide encodes an IL-12B polypeptide wherein the IL-12B polypeptide comprises an amino acid sequence that is 20 identical to SEQ ID NO: 2. In some embodiments, the at least one RNA polynucleotide encodes an IL-18 polypeptide. In some embodiments, the at least one RNA polynucleotide encodes an IL-18 polypeptide wherein the IL-18 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 5. In some embodiments, the at least one RNA polynucleotide encodes an IL-18 25 polypeptide wherein the IL-18 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 5. In some embodiments, the at least one RNA polynucleotide encodes an IL-18 polypeptide wherein the IL-18 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 6. In some embodiments, the at least one RNA polynucleotide encodes an IL-18 30 polypeptide wherein the IL-18 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 6. In some embodiments, the at least one RNA polynucleotide encodes a CCL5 polypeptide. In some embodiments, the at least one RNA polynucleotide encodes a CCL5 polypeptide wherein the CCL5 polypeptide 7 Attorney Docket No.07917-0454WO1 / UMMS 24-66 comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 7. In some embodiments, the at least one RNA polynucleotide encodes a CCL5 polypeptide wherein the CCL5 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 7. In some embodiments, the at least one RNA polynucleotide encodes 5 a CXCL10 polypeptide. In some embodiments, the at least one RNA polynucleotide encodes a CXCL10 polypeptide wherein the CXCL10 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 8. In some embodiments, the at least one RNA polynucleotide encodes a CXCL10 polypeptide wherein the CXCL10 polypeptide comprises an amino acid sequence that is identical 10 to SEQ ID NO: 8. In some embodiments, the at least one RNA polynucleotide encodes an IFNB1 polypeptide. In some embodiments, the at least one RNA polynucleotide encodes an IFNB1 polypeptide wherein the IFNB1 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 9. In some embodiments, the at least one RNA polynucleotide encodes an IFNB1 15 polypeptide wherein the IFNB1 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 9. In some embodiments, the at least one RNA polynucleotide encodes an IL-15 polypeptide. In some embodiments, the at least one RNA polynucleotide encodes an IL-15 polypeptide wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 3. In 20 some embodiments, the at least one RNA polynucleotide encodes an IL-15 polypeptide wherein the IL-15 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 3. In some embodiments, the at least one RNA polynucleotide encodes an IL-15 polypeptide wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 4. In 25 some embodiments, the at least one RNA polynucleotide encodes an IL-15 polypeptide wherein the IL-15 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 4. In some embodiments, a composition disclosed herein can further comprise at least one RNA polynucleotide that encodes a tumor antigen polypeptide. In some 30 embodiments, the least one RNA polynucleotide encodes a tumor antigen polypeptide selected from the group consisting of mesothelin (MSLN), Mucin-1 (Muc1), prostate- specific membrane antigen (PSMA), epidermal growth factor receptor (EGFR), receptor tyrosine kinase like orphan receptor 1 (ROR1), transferrin (TR), 8 Attorney Docket No.07917-0454WO1 / UMMS 24-66 carcinoembryonic antigen (CEA), encode tyrosine kinase-type cell surface receptor HER2 (HER2), tumor-associated calcium signal transducer 2 (TROP2), claudin 18.2 (CLDN18.2), mucin-16 (Muc16), prominin-1 (CD133), and cadherin 3 (CDH3). In some embodiments, the least one RNA polynucleotide encodes a tumor antigen 5 polypeptide selected from the group consisting of MSLN, Muc1, and PSMA. In some embodiments, the composition comprises three RNA polynucleotides that encode for the tumor antigen polypeptides MSLN, Muc1, and PSMA. In some embodiments, the at least one RNA polynucleotide encodes a MSLN polypeptide. In some embodiments, the at least one RNA polynucleotide encodes a MSLN polypeptide 10 wherein the MSLN polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 10. In some embodiments, the at least one RNA polynucleotide encodes a MSLN polypeptide wherein the MSLN polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 10. In some embodiments, the at least one RNA polynucleotide encodes a Muc1 polypeptide. In 15 some embodiments, the at least one RNA polynucleotide encodes a Muc1 polypeptide wherein the Muc1 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 11. In some embodiments, the at least one RNA polynucleotide encodes a Muc1 polypeptide wherein the Muc1 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 11. In some embodiments, 20 the at least one RNA polynucleotide encodes a PSMA polypeptide. In some embodiments, the at least one RNA polynucleotide encodes a PSMA polypeptide wherein the PSMA polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 12. In some embodiments, the at least one RNA polynucleotide encodes a PSMA polypeptide wherein the PSMA polypeptide 25 comprises an amino acid sequence that is identical to SEQ ID NO: 12. In some embodiments, the at least one RNA polynucleotide comprises a messenger RNA (mRNA) polynucleotide. In some embodiments, the at least one RNA polynucleotide comprises a capped RNA. In some embodiments, the RNA polynucleotide is capped using a 7-methylguanosine (m⁷G) cap analog. In some 30 embodiments, the at least one RNA polynucleotide comprises a polyadenylated RNA. In some embodiments, the at least one RNA comprises at least one modification. In some embodiments, the modified RNA comprises at least one modified nucleoside. In some embodiments, the at least one modified nucleoside is a uridine nucleoside. In 9 Attorney Docket No.07917-0454WO1 / UMMS 24-66 some embodiments, the modified uridine nucleoside is N1-methylpseudouridine-5′- triphosphate. In some embodiments, the composition comprises less than 5% (e.g., less than about 5%, 4%, 3%, 2%, 1%, 0.5% or is essentially free of) double-stranded RNA. 5 Provided herein are also pharmaceutical compositions comprising (i) a pharmaceutically acceptable carrier, and (ii) at least one RNA polynucleotide selected from any of the RNA polynucleotides disclosed herein that encode a cytokine polypeptide; at least one RNA polynucleotide selected from any of the RNA polynucleotides disclosed herein that encode a tumor antigen polypeptide; or at least 10 one RNA polynucleotide selected from any of the RNA polynucleotides disclosed herein that encode a cytokine polypeptide and at least one RNA polynucleotide selected from any of the RNA polynucleotides disclosed herein that encode a tumor antigen polypeptide. Additionally, provided herein are cancer vaccine compositions (e.g., a cancer 15 vaccine) comprising (i) a pharmaceutically acceptable carrier, and (ii) at least one RNA polynucleotide selected from any of the RNA polynucleotides disclosed herein that encode a cytokine polypeptide; at least one RNA polynucleotide selected from any of the RNA polynucleotides disclosed herein that encode a tumor antigen polypeptide; or at least one RNA polynucleotide selected from any of the RNA 20 polynucleotides disclosed herein that encode a cytokine polypeptide and at least one RNA polynucleotide selected from any of the RNA polynucleotides disclosed herein that encode a tumor antigen polypeptide. In some embodiments, the cancer vaccine comprises at least one adjuvant. In some embodiments, at least one adjuvant can be co-administered with the cancer vaccine of the present disclosure. 25 Also provided herein are lipid nanoparticles. In some embodiments, a lipid nanoparticle of the present disclosure comprises: at least one phospholipid; at least one PEG lipid; at least one structural lipid; at least one ionizable lipid; and an RNA polynucleotide(s) disclosed herein, wherein the RNA polynucleotide(s) (i) is at least one RNA polynucleotide selected from any of the RNA polynucleotides disclosed 30 herein that encode a cytokine polypeptide; (ii) is at least one RNA polynucleotide selected from any of the RNA polynucleotides disclosed herein that encode a tumor antigen polypeptide, or (iii) includes at least one RNA polynucleotide selected from any of the RNA polynucleotides disclosed herein that encode a cytokine polypeptide 10 Attorney Docket No.07917-0454WO1 / UMMS 24-66 and at least one RNA polynucleotide selected from any of the RNA polynucleotides disclosed herein that encode a tumor antigen polypeptide (e.g., at least two RNA polynucleotides). In some embodiments, (i) the at least one phospholipid is 1,2- distearoyl-sn-glycero-3-phosphocholine (DSPC); (ii) the at least one PEG lipid 1,2- 5 dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG); (iii) the at least one structural lipid is cholesterol; and / or (iv) the at least one ionizable lipid is D- Lin-MC3-DMA (MC3). In some embodiments, the at least one RNA polynucleotide is encapsulated within the lipid nanoparticle. In some embodiments, a composition (e.g., a pharmaceutical composition) 10 contemplated herein can comprise (i) at least one lipid nanoparticle that encapsulates at least one RNA polynucleotide that encodes a cytokine polypeptide as disclosed herein, (ii) at least one lipid nanoparticle that encapsulates at least one RNA polynucleotide that encodes a tumor antigen polypeptide as disclosed herein, (iii) at least one lipid nanoparticle that encapsulates at least one RNA polynucleotide that 15 encodes a cytokine polypeptide as disclosed herein and also encapsulates at least one RNA polynucleotide that encodes a tumor antigen as disclosed herein, or (iv) any combination of the lipid nanoparticles as described in (i)-(iii). Provided herein are methods of treating a cancer in a subject. In some embodiments, methods of treating a cancer in a subject comprise administering a 20 therapeutically effective amount of any of the compositions disclosed herein, any of the pharmaceutical compositions disclosed herein, any of the cancer vaccines disclosed herein, and / or any of the lipid nanoparticles disclosed herein. In some embodiments, the cancer treated according to the methods disclosed herein comprises a cold tumor. In some embodiments, the cancer treated according to the methods 25 disclosed herein is ovarian cancer, breast cancer, brain cancer, prostate cancer, or pancreatic cancer. In some embodiments, the pancreatic cancer is selected from the group consisting of pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, adenosquamous carcinoma, colloid carcinoma, and pancreatic neuroendocrine tumors (NETs). In some embodiments, the pancreatic cancer is 30 PDAC. In some embodiments, the administering of a composition comprising at least one RNA polynucleotide selected from the group consisting of IL-12, IL-15, IL-18, IFNB1, CXCL10, and CCL5 occurs before, after, or at the same time as the 11 Attorney Docket No.07917-0454WO1 / UMMS 24-66 administering of a composition comprising at least one RNA polynucleotide selected from the group consisting of MSLN, Muc1, PSMA, EGFR, ROR1, TR, CEA, HER2, TROP2, CLDN18.2, Muc16, CD133, and CDH3. In some embodiments, the administering is local by intratumoral administration or systemic by intravenous 5 administration. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also 10 be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. As used herein, the term “about” means plus or minus 10%. 15 Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS FIGS. 1A-1G: Intratumoral delivery of cytokine-encoding mRNA cocktail drove robust local expression of cytokines and chemokines in orthotopic PDAC 20 models. FIG. 1A depicts a schematic of in vitro mRNA synthesis and purification. FIG. 1B depicts an experimental outline of orthotopic KPC1 transplant and intratumoral administration of mRNA cocktail encoding IL-12, IL-15, IL-18, IFNB1, CXCL10, and CCL5 (10 μg per mRNA; total 60 μg) or scramble mRNA (10 μg) for cytokine array analysis. FIG. 1C shows cytokine array results of KPC1 tumors at 24 25 hours (h), 48 h, and 96 h post single intratumoral cytokine mRNA cocktail or scramble mRNA administration (n=3-8 independent samples per group). FIG. 1D shows cytokine array results of livers from KPC1 tumor-bearing mice at 24 h post single intratumoral cytokine mRNA cocktail or scramble mRNA administration (n=5 independent samples per group). FIG. 1E shows cytokine array results of blood from 30 KPC1 tumor-bearing mice at 24 h post single intratumoral cytokine mRNA cocktail or scramble mRNA administration (n=5 independent samples per group). FIG. 1F shows body weight change in KPC1 tumor-bearing mice as measured at 24 h, 48 h, and 72 h post single intratumoral cytokine mRNA cocktail or scramble mRNA 12 Attorney Docket No.07917-0454WO1 / UMMS 24-66 administration (n=5 independent samples per group). FIG. 1G shows representative images of co-immunofluorescent (IF) staining of KPC1 orthotopic tumors collected at 6 h post-intratumoral GFP-encoding mRNA or scramble mRNA administration (10 μg per mouse) (n=3 independent samples per group). 5 FIGS. 2A-2L: In vitro and in vivo assays revealed distinct roles of individual cytokines and chemokines in facilitating anti-tumor immune effects within the PDAC TME. FIG. 2A depicts an experimental outline for in vitro NK cell migration and activation assays. FIG. 2B shows the absolute number of NK cells that migrated following co-culture with KPC1 cell lines transfected with either single cytokine 10 mRNAs (0.5 μg), variable cocktails of 4, 5, or 6 cytokines (0.5 μg per cytokine), or scramble mRNA (3 μg) (n=3 independent samples per group). FIG. 2C shows flow cytometry analysis of the NK cell activation marker (IFNγ) following co-culture with KPC1 cell lines transfected with either single cytokine mRNAs (0.5 μg), variable cocktails of 4, 5, or 6 cytokines (0.5 μg per cytokine), or scramble mRNA (3 μg) (n=3 15 independent samples per group). FIG. 2D depicts an experimental outline for in vitro CD8+T cell migration and activation assays. FIG. 2E shows the absolute number of CD8+T cells that migrated following co-culture with KPC1 cell lines transfected with either single cytokine mRNAs (0.5 μg), variable cocktails of 4, 5, or 6 cytokines (0.5 μg per cytokine), or scramble mRNA (3 μg) (n=3 independent samples per group). 20 FIG. 2F shows flow cytometry analysis of the CD8+T cell activation marker (IFNγ) following co-culture with KPC1 cell lines transfected with either single cytokine mRNAs (0.5 μg), variable cocktails of 4, 5, or 6 cytokines (0.5 μg per cytokine), or scramble mRNA (3 μg) (n=3 independent samples per group). FIG. 2G shows representative histograms (left) and quantification of mean fluorescent intensity (MFI; 25 right) of MHC-I (H-2kb) expression on KPC1 cells following mRNA transfections (conditions as shown in FIG. 2G; n=3 independent samples per group). FIG. 2H depicts an experimental outline for in vivo flow cytometry studies. FIG. 2I shows flow cytometry analysis of total NK cell numbers at 96 h (day 4) following intratumoral administration of single cytokine mRNAs or scramble mRNA (10 μg per 30 mouse) (n=3-9 independent samples per group). FIG. 2J shows flow cytometry analysis of NK cell activation marker (GZMB) at 96 h (day 4) following intratumoral administration of single cytokine mRNAs or scramble mRNA (10 μg per mouse) (n=3-9 independent samples per group). FIG. 2K shows flow cytometry analysis of 13 Attorney Docket No.07917-0454WO1 / UMMS 24-66 total CD8+T cell numbers at 96 h (day 4) following intratumoral administration of single cytokine mRNAs or scramble mRNA (10 μg per mouse) (n=3-9 independent samples per group). FIG. 2L shows flow cytometry analysis of CD8+T cell activation marker (GZMB) at 96 h (day 4) following intratumoral administration of single 5 cytokine mRNAs or scramble mRNA (10 μg per mouse) (n=3-9 independent samples per group). FIGS. 3A-3L: Intratumoral administration of cytokine-encoding mRNA potentiateD anti-tumor immune response and prolongED survival in orthotopic PDAC models. FIG. 3A depicts an experimental outline for in vivo flow cytometry 10 studies. Mice bearing orthotopic KPC1 tumors were intratumorally administered either a cytokine mRNA cocktail (10 μg of IL-12, IL-15, IL-18, IFNB1, CXCL10, CCL5; 60 μg total), IL-12 mRNA alone (60 μg), or scramble mRNA (60 μg) at days 0, 3, 6, and 9 following flow analysis at day 12 (n= 4-8 independent samples per group). FIG. 3B shows flow cytometry analysis of total CD45+immune cells on day 15 12. FIG. 3C shows flow cytometry analysis of total CD8+T cell numbers on day 12. FIG. 3D shows flow cytometry analysis of total CD4+T cell numbers on day 12. FIG. 3E shows flow cytometry analysis of CD8+T cell activation markers (IFNγ and GZMB) on day 12. FIG. 3F shows flow cytometry analysis of CD8+T cell memory markers on day 12. FIG. 3G shows flow cytometry analysis of total NK cell numbers 20 on day 12. FIG. 3H shows flow cytometry analysis of NK cell activation markers (IFNγ and GZMB) on day 12. FIG. 3I shows representative images of IHC staining of SMA+cells in KPC1 orthotopic tumors on day 12. FIG. 3J shows quantification of SMA+cells in KPC1 orthotopic tumors on day 12. FIG. 3K shows the response to intratumoral cytokine mRNA administration as measured by ultrasound after 2 weeks 25 of treatment (n=9-10 independent samples per group). FIG. 3L shows Kaplan-Meier survival curves of KPC1 orthotopic transplant mice treated with intratumoral cytokine mRNA cocktail (10 μg of IL-12, IL-15, IL-18, IFNB1, CXCL10, CCL5; 60 μg total), IL-12 mRNA single (60 μg), or scramble mRNA (60 μg) two times a week until end of study (n=9-10 independent samples per group). 30 FIGS. 4A-4K: Neoantigen-driven T cell immunity enhanceD the efficacy of cytokine mRNA therapy in PDAC. FIG. 4A depicts an experimental outline for in vivo flow cytometry studies. Mice bearing orthotopic KPC 2838c3 tumors were intratumorally administered either a cytokine mRNA cocktail (10 μg of IL-12, IL-18, 14 Attorney Docket No.07917-0454WO1 / UMMS 24-66 IFNB1, CXCL10, CCL5; 50 μg total), or scramble mRNA (50 μg) at days 0, 3, 6, and 9 following flow analysis at day 12 (n=8 independent samples per group). FIG. 4B shows flow cytometry analysis of total CD45+immune cells on day 12. FIG. 4C shows flow cytometry analysis of total CD8+T cell numbers on day 12. FIG. 4D 5 shows flow cytometry analysis of total CD4+T cell numbers on day 12. FIG. 4E shows flow cytometry analysis of CD8+T cell activation markers (IFNγ and GZMB) on day 12. FIG. 4F shows flow cytometry analysis of CD4+T cell activation markers (IFNγ and GZMB) on day 12. FIG. 4G shows flow cytometry analysis of CD8+T cell memory markers on day 12. FIG. 4H shows flow cytometry analysis of total NK cell 10 numbers on day 12. FIG. 4I shows flow cytometry analysis of NK cell activation markers (IFNγ and GZMB) on day 12. FIG. 4J shows flow cytometry analysis of Cd11b+Gr-1+myeloid-derived suppressor cells on day 12. FIG. 4K shows flow cytometry analysis of Cd11b- Cd11c+MHC-II+Cd103a+dendritic cells on day 12. FIGS. 5A-5K: Co-delivery of cytokine- and antigen-encoding mRNAs elicited 15 a comprehensive anti-tumor immune response mediated by cytotoxic T cells and NK cells. FIG. 5A depicts a schematic illustration of the combination of antigen-encoding and cytokine-encoding mRNAs. FIG. 5B shows representative images of IHC staining and quantification of Muc-1+, MSLN+, and PSMA+cells in KPC1 orthotopic tumors. FIG. 5C depicts an experimental outline for in vivo flow cytometry studies. 20 Mice bearing orthotopic KPC1 tumors were intratumorally administered either a cytokine mRNA cocktail (10 μg of IL-12, IL-15, IL-18, IFNB1, CXCL10, CCL5; 50 μg total), an antigen mRNA cocktail (10 μg of Muc-1, MSLN, PSMA; 30 μg total), a combination of cytokine and antigen mRNA (10 μg each; 80 μg total) or scramble mRNA (80 μg) at days 0, 3, 6, and 9 following flow analysis at day 12 (n= 6-8 25 independent samples per group). FIG. 5D shows flow cytometry analysis of total CD45+immune cells on day 12. FIG. 5E shows flow cytometry analysis of total CD8+T cell numbers on day 12. FIG. 5F shows flow cytometry analysis of CD8+T cell activation markers (IFNγ and GZMB) on day 12. FIG. 5G shows flow cytometry analysis of CD8+T cell memory markers on day 12. FIG. 5H shows flow cytometry 30 analysis of total NK cell numbers on day 12. FIG. 5I shows flow cytometry analysis of NK cell activation markers (IFNγ and GZMB) on day 12. FIG. 5J shows flow cytometry analysis of Cd11b- Cd11c+MHC-II+Cd103a+dendritic cells on day 12. FIG. 5K shows representative images of hematoxylin and eosin (H&E) staining of 15 Attorney Docket No.07917-0454WO1 / UMMS 24-66 KPC1 orthotopic tumors on day 12 showing necrosis. Quantification of necrosis is included in the white insert. FIGS. 6A-6I: Single dose of antigen and cytokine mRNA combination therapy sustained tumor control and extended survival in orthotopic models of PDAC. FIG. 5 6A depicts an experimental outline for the survival study. Mice bearing orthotopic KPC 2838c3 tumors were intratumorally administered with a single dose of either a cytokine mRNA cocktail (10 μg of IL-12, IL-18, IFNB1, CXCL10, CCL5; 50 μg total) or scramble mRNA (50 μg) at day 0 (n=8 independent samples per group). FIG. 6B shows a waterfall plot of the response of KPC 2838c3 orthotopic tumors with 10 indicated treatment as mentioned in FIG. 6A. FIG. 6C shows Kaplan-Meier survival curves of KPC 2838c3 orthotopic transplant mice with indicated treatment as mentioned in FIG. 6A. FIG. 6D depicts an experimental outline for the survival study. Mice bearing orthotopic KPC1 tumors were intratumorally administered with a single dose of either a cytokine mRNA cocktail (10 μg of IL-12, IL-15, IL-18, IFNB1, 15 CXCL10, CCL5; 50 μg total), combination of cytokine mRNA and antigen mRNA (10 μg of IL-12, IL-18, IFNB1, CXCL10, CCL5, Muc-1, MSLN, PSMA; 80 μg total) or scramble mRNA (80 μg) at day 0 (n=5-6 independent samples per group). FIG. 6E shows a waterfall plot of the response of KPC1 orthotopic tumors with indicated treatment as mentioned in FIG. 6D. FIG. 6F shows Kaplan-Meier survival curves of 20 KPC1 orthotopic transplant mice with indicated treatment as mentioned in FIG. 6D. FIG. 6G shows Kaplan-Meier survival curves of KPC1 orthotopic transplant mice with indicated treatment as mentioned in FIG. 6D. FIG. 6H shows representative images of IHC staining and quantification of CD8+T and NKp46+cells in KPC1 orthotopic tumors. FIG. 6I shows Kaplan-Meier survival curves of KPC1 orthotopic 25 transplant mice treated with or without NK (250 μg) and T cell (200 μg) depleting antibodies two times a week. FIGS. 7A-7L: LNP-based mRNA delivery significantly curtailed tumor progression in genetically engineered models of PDAC. FIG. 7A depicts an experimental outline of KPC GEMMs and LNP-based administration of mRNA 30 cocktail encoding IL-12, IL-18, IFNB1, CXCL10, and CCL5 (10 μg per mRNA; total 50 μg) or scramble mRNA (50 μg) for cytokine array analysis. FIG. 7B shows cytokine array results of KPC GEMM tumors at 24 h and 48 h post single systemic LNP encapsulated cytokine mRNA cocktail or scramble mRNA administration (n=3- 16 Attorney Docket No.07917-0454WO1 / UMMS 24-66 8 independent samples per group). FIG. 7C shows representative images of IHC staining and quantification of Muc-1+, MSLN+, and PSMA+cells in KPC GEMM tumors. FIG. 7D depicts an experimental outline for in vivo histochemistry analysis. Mice bearing KPC GEMM tumors were systemically administered either a LNP- 5 encapsulated cytokine and antigen combination cocktail (10 μg of IL-12, IL-15, IL- 18, IFNB1, CXCL10, CCL5, MSLN Muc-1, PSMA; 80 μg total) or scramble mRNA (80 μg) at days 0 and 7, following IHC and H&E analysis at day 14 (n=5 independent samples per group). FIG. 7E shows representative images of IHC staining of CD3+T, CD8+T, NKp46+, and GZMB+cells in KPC GEMM tumors. FIG. 7F shows 10 quantification of CD3+T, CD8+T, NKp46+, and GZMB+cells in KPC GEMM tumors. FIG. 7G shows representative images from a histopathological analysis of KPC GEMM tumors at day 14 following two doses of LNP-encapsulated cytokine and antigen combination or scramble mRNA. FIG. 7H shows a waterfall plot of the response of KPC1 orthotopic tumors with indicated treatment as mentioned in FIG. 15 7D (n=10-13 independent samples per group). FIG. 7I shows representative ultrasound images of KPC1 GEMM tumors before treatment and after 2 or 8 weeks of treatment with a combined antigen and cytokine mRNA cocktail. PDAC tumors are outlined in white. FIG. 7J shows Kaplan-Meier survival curves of KPC GEMM mice with indicated treatment as mentioned in FIG. 7D. Complete responders were put off 20 treatment at Day 75. FIG. 7K shows a waterfall plot of the tumor volume change from day 0 (first dose) vs day 14 (after two doses) of KPC1 GEMM tumors after treatment with either scramble mRNA (80 μg), either a LNP-encapsulated cytokine and antigen combination cocktail (10 μg of IL-12, IL-15, IL-18, IFNB1, CXCL10, CCL5, MSLN Muc-1, PSMA; 80 μg total), or a LNP-encapsulated the antigen25 cocktail (10 μg of MSLN Muc-1, PSMA; 30 μg total) (n=2). FIG. 7L shows Kaplan- Meier survival curves of KPC GEMM mice treated with either scramble mRNA (80 μg), either a LNP-encapsulated cytokine and antigen combination cocktail (10 μg of IL-12, IL-15, IL-18, IFNB1, CXCL10, CCL5, MSLN Muc-1, PSMA; 80 μg total), or a LNP-encapsulated the antigen cocktail (10 μg of MSLN Muc-1, PSMA; 30 μg total) 30 (n=2). Complete responders were put off treatment at Day 75 FIG. 8A: Purified cytokine-encoding mRNAs (0.5 μg per cytokine; 3 μg total) transfected into KPC PDAC tumor cell lines (KPC1) in vitro revealed a multi-fold increase in levels of all six cytokines / chemokines at 24 h post-transfection (n=3). 17 Attorney Docket No.07917-0454WO1 / UMMS 24-66 FIG. 8B: Cytokine and chemokine induction in KPC1 cells following either trametinib (MEK inhibitor) and palbociclib (CDK4 / 6 inhibitor) treatment (T / P) or vehicle treatment (n=3 to 5). FIG. 8C: Cytokine and chemokine induction in cancer-associated fibroblasts 5 (CAFs) in vitro at 24 h post-transfection of mRNA cocktail encoding IL-12, IL-15, IL-18, IFNB1, CXCL10, and CCL50.5 μg per mRNA; total 3 μg) or scramble mRNA (3 μg). FIG. 8D: Array results of KPC1 tumors at 48 h, and 96 h post single intratumoral cytokine 6-mRNA cocktail (IL-12, IL-15, IL-18, IFNB1, CXCL10, and 10 CCL5) or scramble mRNA administration (n= 3-5). FIG. 8E: Increased levels of GM-CSF and the chemokines MIG (CXCL9), and MIP-1α (CCL3) were observed at 48 h and 96 h after a single intratumoral administration of the cytokine 6-mRNA cocktail (IL-12, IL-15, IL-18, IFNB1, CXCL10, and CCL5) to KPC1 tumor-bearing mice (n= 3-5). 15 FIG. 8F: To optimize dosing, 10 µg versus 60 µg of IL-12 mRNA was administered to KPC1 tumor-bearing mice and IL-12 expression was assessed (n=5). FIG. 8G: Cytokine levels were measured in the orthotopic model 24 h after administering 10 µg free IL-12 mRNA, 10 µg free scrambled mRNA, or 10 µg LNP- encapsulated IL-12 mRNA (n=5). 20 FIGS. 9A-9F show flow cytometry analysis of: the NK cell activation marker, IFNγ (FIG. 9A); the CD8+T cell activation marker, IFNγ (FIG. 9B); total CD4+T cell numbers (FIG. 9C); the CD4+T cell activation markers, GZMB and IFNγ (FIG. 9D); Cd11b+Gr-1+myeloid-derived suppressor cells (MDSCs) (FIG. 9E); and Cd11b- Cd11c+MHC-II+Cd103a+dendritic cells (DCs) (FIG. 9F) 96 h (day 4) after 25 intratumoral administration of a single cytokine mRNA (i.e., monotherapy) (IL-12, IL-15, IL-18, IFNB1, CXCL10, or CCL5) or a scramble mRNA (10 μg mRNA per mouse) to an orthotopic PDAC mouse model (n=3-9). FIGS. 10A-10E: Mice bearing orthotopic KPC1 tumors were intratumorally administered either a cytokine mRNA cocktail (10 μg of IL-12, IL-15, IL-18, IFNB1, 30 CXCL10, CCL5; 60 μg total), IL-12 mRNA alone (60 μg), or scramble mRNA (60 μg) at days 0, 3, 6, and 9 following flow analysis at day 12. Shown are flow cytometry analyses of: CD4+T cell activation markers (IFNγ AND GZMB) (FIG. 10A); CD8+T cell exhaustion markers PD-1, CTLA-4, LAG-3, and TIGIT (FIG. 18 Attorney Docket No.07917-0454WO1 / UMMS 24-66 10B); Cd11b+Gr-1+myeloid-derived suppressor cells (MDSCs) (FIG. 10C); and Cd11b- Cd11c+MHC-II+Cd103a+dendritic cells (DCs) (FIG. 10D). FIG. 10E shows representative images of KPC1 tumors harvested from the three treatment groups subjected to IHC and stained with the tumor cell proliferation marker, Ki67, and the 5 apoptosis marker, CC3 (n=4-8). FIG. 10F shows clonogenic assays performed on KPC1 tumor cells and CAFs in vitro 7 days following mRNA transfection with either the cytokine mRNA cocktail (0.5 μg of IL-12, IL-15, IL-18, IFNB1, CXCL10, CCL5; 3 μg total) or scramble mRNA (3 μg) (n=3). 10 FIG. 11: Mice bearing orthotopic KPC 2838c3 tumors were intratumorally administered either a cytokine mRNA cocktail (10 μg of IL-12, IL-18, IFNB1, CXCL10, CCL5; 50 μg total), or scramble mRNA (50 μg) at days 0, 3, 6, and 9 following flow analysis at day 12. Shown is a flow cytometry analysis of CD8+T cell exhaustion markers PD-1, CTLA-4, LAG-3, and TIGIT (n=8) 15 FIG. 12A depicts an experimental outline for an ex vivo stimulation assay. FIG. 12B shows antigen-specific activation of T cells from vaccinated tumor-bearing mice confirmed by a marked increase in IFNγ⁺ GZMB⁺ CD8⁺ T cells following exposure to antigen-mRNA-pulsed splenocytes as measured by flow cytometry (n=3). FIGS. 12C-12F: Mice bearing orthotopic KPC1 tumors were intratumorally 20 administered either a cytokine mRNA cocktail (10 μg of IL-12, IL-15, IL-18, IFNB1, CXCL10, CCL5; 50 μg total), an antigen mRNA cocktail (10 μg of Muc-1, MSLN, PSMA; 30 μg total), a combination of cytokine and antigen mRNA (10 μg each; 80 μg total) or scramble mRNA (80 μg) at days 0, 3, 6, and 9 following flow analysis at day 12 (n= 6-8 independent samples per group). Shown are flow cytometry analyses 25 of: total CD4+T cell numbers (FIG. 12C); the CD4+T cell activation markers, GZMB and IFNγ (FIG. 12D); CD8+T cell exhaustion markers PD-1, CTLA-4, LAG- 3, and TIGIT (FIG. 12E); and Cd11b+Gr-1+myeloid-derived suppressor cells (MDSCs) (FIG. 12F). FIGS. 13A-13H: A cytokine 5-mRNA cocktail (10 μg of IL-12, IL-15, IL-18, 30 IFNB1, CXCL10, CCL5; 50 μg total) was encapsulated into LNPs to enable systemic delivery via tail vein injection. The resulting mRNA LNPs (“NPs”) were characterized by size (FIG. 13A), zeta potential (FIG. 13B), encapsulation efficiency (FIG. 13C) and mRNA concentration (FIG. 13D). Following systemic administration 19 Attorney Docket No.07917-0454WO1 / UMMS 24-66 of the mRNA LNPs to genetically engineered mouse models (GEMMs) of PDAC via the tail vein (i.e., intravenously), cytokine secretion profiles were assessed in liver (FIG. 13E) and blood (FIG. 13F). FIG. 13G shows no change in body weight in GEMMs following systemic delivery of mRNA LNPs. FIG. 13H shows 5 representative images of hematoxylin and eosin (H&E) staining of pancreatic tissue in GEMMs at day 14 following two doses of LNP-encapsulated cytokine and antigen combination or scramble mRNA. DETAILED DESCRIPTION Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy 10 (1, 2). Most patients are not eligible for surgical resection and standard-of-care chemotherapy and radiotherapy regimens have limited efficacy (3-7). Moreover, rampant immune suppression and exclusion of cytotoxic Natural Killer (NK) and T lymphocytes in the PDAC TME, coupled with weak tumor immunogenicity, contribute to de novo resistance to immune checkpoint blockade (ICB) inhibitors 15 targeting PD-1 / PD-L1 and / or CTLA-4 that have otherwise demonstrated remarkable success in treating other chemo-resistant malignancies such as non-small cell lung cancer (NSCLC) and melanoma. Hence, there is a pressing need for innovative therapeutic strategies to tackle the suppressive TME of PDAC and achieve durable tumor control. 20 KRAS mutations are present in >90% of PDAC lesions and drive disease onset and progression intrinsically by promoting tumor cell growth and survival and extrinsically through remodeling the surrounding TME to mediate immune evasion (8). We have previously shown that targeting signaling downstream of KRAS with a combination of the MEK inhibitor trametinib and CDK4 / 6 inhibitor palbociclib (T / P) 25 can promote tumor vascularization and CD8+T cell accumulation in the TME, leading to increased uptake and sensitivity to chemotherapy and anti-PD-1 ICB (9). These anti-tumor effects were mediated in part through the induction of cellular senescence and its accompanying senescence-associated secretory phenotype (SASP), a collection of hundreds of pleiotropic cytokines, growth and angiogenic factors, 30 matrix metalloproteinases, and lipid species that can remodel the TME and in particular immune responses in dynamic ways (10). Indeed, combining these senescence-inducing therapies with EZH2 inhibitors or lipid nanoparticle (LNP)- loaded STING and TLR4 agonists to further enhance the pro-inflammatory cytokine 20 Attorney Docket No.07917-0454WO1 / UMMS 24-66 arm of the SASP produced robust anti-tumor NK and CD8+T cell immunity that culminated in even complete responses in preclinical PDAC mouse models (11, 12). Blockade of different SASP programs revealed key interleukins (IL-12, IL-15, IL-18), interferons (IFNB), and chemokines (CCL2, CXCL9, CXCL10, CXCL11) were 5 necessary for anti-tumor NK and T cell immunity in PDAC following senescence induction. Cytokines are a diverse group of small proteins that act as signaling molecules to mediate the recruitment, proliferation, and activation of various immune cells (13). As cytokine expression is frequently altered in human cancers, cytokine 10 administration or blockade has long been pursued as a therapeutic approach for immunologically treating tumors (14). Dating back to the 1980’s, systemic delivery of recombinant cytokine proteins IFN⍺ or IL-2 that can stimulate innate and adaptive immune responses were some of the first approved immunotherapies for treating immunologically “hot” cancers like melanoma and renal cell carcinoma (15-18). 15 However, the modest efficacy of single cytokine administration combined with the often-severe toxicities elicited by high-dose systemic delivery have limited the clinical utility of these and other cytokines such as IFN^ and IL-12 (19-23). Advances in mRNA therapeutics and drug delivery methods in recent years have offered the opportunity to revisit cytokine therapy for cancer. Indeed, work from a number of 20 groups has shown that multiple cytokine-encoding mRNAs can be delivered intratumorally to elicit potent anti-tumor immune responses without systemic toxicities in melanoma and other immunologically “hot” tumor models, even outperforming recombinant protein approaches (24-26). Unlike hot tumors, cold tumors are not likely to trigger a strong immune25response. Cold tumors tend to be surrounded by cells that suppress immune response. As such, cold tumors are typically hard to treat and usually do not respond to immunotherapy. Non-limiting examples of cold tumors include cancerous tumors of the breast, ovary, prostate, pancreas, and brain (glioblastoma) (see, e.g., National Cancer Institute Dictionary of Cancer Terms (cancer.gov / publications / dictionaries / 30 cancer-terms / def / cold-tumor (accessed May 26, 2025))). As provided in the present disclosure, we established an in vitro transcription (IVT) pipeline for de novo mRNA synthesis and multiplexing to generate multiple mRNAs encoding for interleukins, IFNs, and / or chemokines. Further provided herein are methods of administering 21 Attorney Docket No.07917-0454WO1 / UMMS 24-66 combinations of mRNAs encoding for interleukins, IFNs, and / or chemokines, either as free mRNAs intratumorally or via systemic delivery through LNP encapsulation, for the treatment of a cancer associated with cold tumors (e.g., PDAC). 5 The present disclosure provides polynucleotides (e.g., an RNA, e.g., a mRNA), compositions comprised thereof, and methods of using thereof, for example, to treat a cancer (e.g., a tumor, e.g., a cold tumor). Compositions contemplated herein can include a “cocktail” of RNA polynucleotides that encode one or more polypeptides (e.g., cytokines, e.g., antigens) that remodel the tumor microenvironment 10 (TME) for difficult to treat tumors (e.g., cold tumors, e.g., PDAC). RNA Polynucleotides The compositions as provided in the present disclosure can comprise at least one nucleic acid having an open reading frame encoding at least one polypeptide of interest. In general, the term “nucleic acid” includes any compound and / or substance 15 that comprises a polymer of nucleotides. These polymers are referred to as polynucleotides. In some embodiments, the polynucleotides disclosed herein are ribonucleic acid (RNA) polynucleotides. In some embodiments, an RNA polynucleotide disclosed herein can be a messenger RNA (mRNA) polynucleotide, a modified mRNA polynucleotide, an unmodified RNA polynucleotide, linear RNA, or 20 any combination thereof. In some embodiments, an RNA polynucleotide disclosed herein can be a mRNA polynucleotide. RNA polynucleotides (e.g., mRNA polynucleotides) of the present disclosure can comprise, in 5′-to-3′ order: (1) a 5′ UTR; (2) an open reading frame; and (3) a 3′ UTR. In some embodiments, an RNA polynucleotide (e.g., a mRNA polynucleotide) 25 disclosed herein can further include a 5′ cap. RNAs produced in eukaryotic cells can include a 5′ cap that is added during processing of the pre-mRNA into a mature mRNA (see, e.g., Ramanathan et al. Nucleic Acids Res. 2016. 44(16): 7511-7526). In some embodiments, the 5′ cap comprises a 7-methylguanosine. In some embodiments, the RNA polynucleotide is capped using a 7-methylguanosine (m⁷G) 30 cap analog (see, e.g., FIG. 1A). In some embodiments, the cap is a Cap-0, Cap-1, or Cap-2 structure, optionally modified with 7-methylguanosine and / or 5- methoxyuridine, e.g., produced by co-transcriptional capping technology, mCap, or anti-reverse cap analog (ARCA). In some embodiments the mRNA is synthesized, 22 Attorney Docket No.07917-0454WO1 / UMMS 24-66 e.g., using a method as described in U.S. Pat. Nos. 10494399, 10519189, 10913768C1, 11414453, 11878991, 11578095, and 12103944 to TriLink, relating to Compositions and methods for synthesizing 5'-capped RNAs. See also Ramanathan et al., Nucleic Acids Res. 2016 Sep 19;44(16):7511-26. In some embodiments, an RNA 5 polynucleotide (e.g., a mRNA polynucleotide) disclosed herein can be polyadenylated RNA. In some embodiments, an RNA polynucleotide further includes a polyA tail. In some embodiments, an RNA polynucleotide further includes a 3′ polyA tail (see, e.g., FIG. 1A). The polyA element can be, e.g., from bovine growth hormone (BGH), mutant BGH, herpes simplex virus type 1 thymidine kinase (HSV-TK), SV40, or 10 synthetic (Synt) poly A; see, e.g., Wang et al., Front Bioeng Biotechnol. 2022 Jan 24;10:722722; Eckmann et al., (2011). Wiley Interdiscip. Rev. RNA 2 (3), 348–361. RNA polynucleotides (e.g., mRNA polynucleotides) of the present disclosure can be prepared by in vitro transcription (IVT) according to methods known in the art (see, e.g., Beckert & Masquida, Methods Mol Biol. 2011;703:29-41; Kang et al., Adv 15 Drug Deliv Rev. 2023 Jun 14;199:114961; Dousis et al., Nature Biotechnology volume 41, pages 560–568 (2023); Lee et al., Front. Mol. Biosci.,10 September 2023 Sec. Molecular Diagnostics and Therapeutics Volume 10 – 2023, doi.org / 10.3389 / fmolb.2023.1229246). In some embodiments the mRNA is synthesized, e.g., using a method as described in U.S. Pat. Nos. 10494399, 10519189, 20 10913768C1, 11414453, 11878991, 11578095, and 12103944 to TriLink, relating to compositions and methods for synthesizing 5'-capped RNAs. IVT utilizes a DNA template featuring a promoter (e.g., a T7 promoter) sequence upstream of a sequence of interest. The IVT reaction is generally initiated at a dsDNA but can proceed on a single strand. Once the IVT reaction is complete, the resulting IVT transcripts (e.g., 25 RNA polynucleotides, e.g., mRNA polynucleotides) can be purified from the components of the IVT reaction mixture. In some embodiments, IVT transcripts (e.g., RNA polynucleotides, e.g., mRNA polynucleotides) can be purified to remove double-stranded RNA (dsRNA). In some embodiments, IVT transcripts (e.g., RNA polynucleotides, e.g., mRNA polynucleotides) are purified over a cellulose column. 30 Cellulose purification removes dsRNA because the dsRNA contaminants have a higher affinity for cellulose under certain conditions (e.g., specific salt concentrations). This property allows selective retention of dsRNA on cellulose while ssRNA (e.g., RNA polynucleotides, e.g., mRNA polynucleotides) remains in solution. 23 Attorney Docket No.07917-0454WO1 / UMMS 24-66 In some embodiments, compositions disclosed herein comprise purified RNA polynucleotides (e.g., mRNA polynucleotides). In some embodiments, compositions disclosed herein comprise less than about 5% (e.g., less than about 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5%) double-stranded RNA (dsRNA). 5 RNA polynucleotides (e.g., mRNA polynucleotides) disclosed herein can comprise at least one modification. In some embodiments, an RNA polynucleotide disclosed herein can comprise at least one modified nucleoside. A “nucleoside” refers the structural subunit of nucleic acids, consisting of a nucleobase (a nitrogenous base) covalently attached to a five-carbon sugar (either ribose or deoxyribose). A 10 “nucleotide” refers to a nucleoside, including a phosphate group. Modified nucleotides may by synthesized by any useful method, such as, for example, chemically, enzymatically, or recombinantly, to include one or more modified or non- natural nucleosides. In some embodiments, the at least one modified nucleoside disclosed herein can be chemically modified. In some embodiments, the at least one 15 modified nucleoside disclosed herein can be a chemically modified uridine nucleoside. In some embodiments, the chemical modification is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′- thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1- methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-20 dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy- pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 5-methyluridine, and 2′-O-methyl uridine. In some embodiments, the chemical modification is N1-methylpseudouridine (N1mΨ). In some embodiments, an RNA polynucleotide disclosed herein comprises 25 at least one chemically modified uridine nucleoside (e.g., at least one uridine nucleoside is substituted with N1mΨ). In some embodiments, about 5% to about 99% of the uridine nucleosides in an RNA polynucleotide disclosed herein are chemically modified uridine nucleosides. In some embodiments, at least about or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the uridine 30 nucleosides in an RNA polynucleotide disclosed herein are chemically modified uridine nucleosides. In some embodiments, every uridine nucleoside in an RNA polynucleotide disclosed herein is a chemically modified uridine nucleoside (e.g., every uridine nucleoside is substituted with N1mΨ). In some embodiments, an RNA 24 Attorney Docket No.07917-0454WO1 / UMMS 24-66 polynucleotide disclosed herein comprises at least one modified nucleoside wherein the at least one modified nucleoside is N1-methylpseudouridine-5′-triphosphate. In some embodiments, all of the uridine nucleosides in an RNA polynucleotide disclosed herein are substituted with N1-methylpseudouridine-5′-triphosphate. 5 Polypeptides of Interest The compositions of the present disclosure can comprise RNA polynucleotides encoding at least one polypeptide of interest or fragments thereof, and preferable comprise at least 2 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 or more) different polypeptides of interest or fragments thereof. A “polypeptide” as understood herein 10 refers to a polymer of amino acid residues (natural or unnatural) linked together most often by peptide bonds. As such, a polypeptide can refer to proteins and peptides of any size, structure, or function. In some embodiments, a polypeptide encoded by an RNA polynucleotide (e.g., mRNA polynucleotides) of the present disclosure can be about 5 to about 1,500 amino acids in length. Non-limiting examples of polypeptides 15 can include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, analogs, and variants thereof. In some embodiments, RNA polynucleotides (e.g., mRNA polynucleotides) disclosed herein can comprise a nucleotide sequence (e.g., an open reading frame (ORF)) encoding at least one polypeptide of interest. In some embodiments, RNA 20 polynucleotides (e.g., mRNA polynucleotides) disclosed herein can comprise a nucleotide sequence (e.g., an ORF) encoding at least one variant of the polypeptide of interest. A variant of the polypeptide of interest refers to a polypeptide having an amino acid sequence that differs from a native or reference amino acid sequence. The amino acid sequence of such variant polypeptides can have substitutions, deletions, 25 and / or insertions at certain positions within the amino acid sequence, as compared to a native or reference sequence. Variant polypeptides of the present disclosure can possess at least about 50% identity to a native or reference sequence. In the present disclosure, the percentage of “sequence identity” between two sequences can be determined by comparing two such sequences over their entire 30 length by global pairwise alignment using the algorithm of Needleman and Wunsch (J. Mol. Biol. 48:443 (1970)), e.g., using the program Needle (EMBOSS) with the BLOSUM62 matrix and the following parameters: gap open=10, gap extend=0.5, end 25 Attorney Docket No.07917-0454WO1 / UMMS 24-66 gap penalty=false, end gap open=10, end gap extend=0.5 (which are standard settings). Cytokine Polypeptides Cytokines and chemokines (a family of low molecular weight chemotactic 5 cytokines) are pleiotropic polypeptides that control the development of immune cells and responses mediated by immune cells (see, e.g., Chauhan et al., Cytokine. 2021 Sep;145:155458; Cameron & Kelvin. Cytokines, Chemokines and Their Receptors. In: MADAME CURIE BIOSCIENCE DATABASE [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from ncbi.nlm.nih.gov / books / NBK6294 / (accessed 10 May 27, 2025)). In some embodiments, an RNA polynucleotide (e.g., a mRNA polynucleotide) disclosed herein can encode at least one cytokine polypeptide or variant thereof. An RNA polynucleotide of the present disclosure can encode interleukin 12 (IL-12), a subunit of IL-12, a variant of IL-12, and / or an isoform of IL-12. IL-12 15 is a disulfide-linked heterodimer composed of a 35 kD subunit (interleukin-12 subunit alpha, or “IL-12A”) encoded by the IL12A gene, and a 40 kD cytokine subunit (interleukin-12 subunit beta of “IL-12B”) encoded by the IL12B gene. The active heterodimer of IL-12 (referred to as “p70”), and a homodimer of p40 are formed following protein synthesis. The amino acid sequence of IL-12A (Homo sapiens) is:20 MWPPGSASQPPPSPAAATGLHPAARPVSLQCRLSMCPARSLLLVATLVLLDH LSLARNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEID HEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMAL CLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNS ETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS (SEQ ID25NO: 1) The amino acid sequence of IL-12B (Homo sapiens) is: MCHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDAPGEMVVLTCDT PEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLL HKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSV 30 KSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPI EVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPD TWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQD RYYSSSWSEWASVPCS (SEQ ID NO: 2) In some embodiments, an RNA polynucleotide disclosed herein can encode an 35 IL-12 polypeptide, a subunit IL-12 polypeptide, and / or an IL-12 isoform polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL- 26 Attorney Docket No.07917-0454WO1 / UMMS 24-66 12A polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-12B polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode both an IL-12A polypeptide and an IL-12B polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode an 5 IL-12A polypeptide wherein the IL-12A polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 1. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-12A polypeptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, an RNA polynucleotide disclosed herein can 10 encode an IL-12A polypeptide consisting of the amino acid sequence of SEQ ID NO:1. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-12B polypeptide wherein the IL-12B polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% 15 identical to SEQ ID NO: 2. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-12B polypeptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-12B polypeptide consisting of the amino acid sequence of SEQ ID NO: 2. 20 An RNA polynucleotide of the present disclosure can encode interleukin 15 (IL-15), a subunit of IL-15, a variant of IL-15, and / or an isoform of IL-15. IL-15 is a 15–17-kDa member of the four-α-helix bundle family of cytokines that stimulate T and NK cell proliferation and activity. Two isoforms of interleukin IL-15 exist: one with a short signal peptide (ssP) and another with a long signal peptide (LSP). 25 Isoform 1 is the longer isoform (also known as 48aa(LSP)-IL15) and isoform 2 (also known as (21aa(SSP)-IL15) has a shorter and distinct N-terminus, compared to isoform 1. See, e.g., Kurys et al., J Biol Chem. 2000 Sep 29;275(39):30653-9. The amino acid sequence of isoform 1 of IL-15 (Homo sapiens) is: MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANWVN 30 VISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGD ASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQ MFINTS (SEQ ID NO: 3) The amino acid sequence isoform 2 of IL-15 (Homo sapiens) is: 27 Attorney Docket No.07917-0454WO1 / UMMS 24-66 MVLGTIDLCSCFSAGLPKTEANWVNVISDLKKIEDLIQSMHIDATLYTESDV HPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTES GCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 4) In some embodiments, an RNA polynucleotide disclosed herein can encode an 5 IL-15 polypeptide, a subunit IL-15 polypeptide, and / or an IL-15 isoform polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-15 isoform 1 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-15 isoform 2 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode both an IL-15 isoform 1 polypeptide and10an IL-15 isoform 2 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-15 polypeptide wherein the IL-15 polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 3. In some embodiments, an RNA polynucleotide disclosed herein can 15 encode an IL-15 polypeptide comprising the amino acid sequence of SEQ ID NO: 3. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-15 polypeptide consisting of the amino acid sequence of SEQ ID NO: 3. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-15 polypeptide wherein the IL-15 polypeptide comprises an amino acid sequence20that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 4. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-15 polypeptide comprising the amino acid sequence of SEQ ID NO: 4. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-15 polypeptide consisting of the amino acid sequence of SEQ ID NO: 4. 25 An RNA polynucleotide of the present disclosure can encode interleukin 18 (IL-18), a subunit of IL-18, a variant of IL-18, a precursor of IL-18, and / or an isoform of IL-18. IL-18 is a proinflammatory cytokine synthesized as a 24 kDa inactive precursor (pro-IL-18). The inactive IL-18 precursor can be processed to its active form by caspase-1 and / or caspase-4. Alternative splicing results in two30isoforms. See, e.g., Gaggero et al., Oncogene. 2004 Sep 30;23(45):7552-60. The amino acid sequence of isoform 1 of IL-18 (Homo sapiens) is: MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESDYFGKLESKLSVIRNLN DQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKC EKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSY35EGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 5)28 Attorney Docket No.07917-0454WO1 / UMMS 24-66 The amino acid sequence isoform 2 of IL-18 (Homo sapiens) is: MAAEPVEDNCINFVAMKFIDNTLYFIENLESDYFGKLESKLSVIRNLNDQVL FIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKIS TLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYF 5 LACEKERDLFKLILKKEDELGDRSIMFTVQNED(SEQ ID NO: 6) In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-18 polypeptide, a subunit IL-18 polypeptide, a precursor polypeptide of IL-18, and / or an IL-18 isoform polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-18 isoform 1 polypeptide. In some embodiments,10an RNA polynucleotide disclosed herein can encode an IL-18 isoform 2 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode both an IL-18 isoform 1 polypeptide and an IL-18 isoform 2 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-18 polypeptide wherein the IL-18 polypeptide comprises an amino acid sequence 15 that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 5. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-18 polypeptide comprising the amino acid sequence of SEQ ID NO: 5. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-18 polypeptide consisting of the amino acid sequence of SEQ ID NO: 5.20In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-18 polypeptide wherein the IL-18 polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 6. In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-18 polypeptide comprising the amino acid sequence of SEQ ID NO: 6. 25 In some embodiments, an RNA polynucleotide disclosed herein can encode an IL-18 polypeptide consisting of the amino acid sequence of SEQ ID NO: 6. An RNA polynucleotide of the present disclosure can encode C-C motif chemokine ligand 5 (CCL5) and / or a variant of CCL5. CCL5 (also known as “RANTES”) belongs to the C-C motif chemokine family. See, e.g., Wang et al., Front30Immunol. 2024 Jul 1;15:1421076. The amino acid sequence of CCL5 (Homo sapiens) is: MKVSAAALAVILIATALCAPASASPYSSDTTPCCFAYIARPLPRAHIKEYFY TSGKCSNPAVVFVTRKNRQVCANPEKKWVREYINSLEMS (SEQ ID NO: 7) 29 Attorney Docket No.07917-0454WO1 / UMMS 24-66 In some embodiments, an RNA polynucleotide disclosed herein can encode a CCL5 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode a CCL5 polypeptide wherein the CCL5 polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% 5 identical to SEQ ID NO: 7. In some embodiments, an RNA polynucleotide disclosed herein can encode a CCL5 polypeptide comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments, an RNA polynucleotide disclosed herein can encode a CCL5 polypeptide consisting of the amino acid sequence of SEQ ID NO: 7. An RNA polynucleotide of the present disclosure can encode C-X-C motif 10 chemokine ligand 10 (CXCL10) and / or a variant of CXCL10. CXCL10 is an ELR−CXC chemokine and is also known as interferon-inducible protein-10 (IP-10) (see, e.g., Gao et al., Mediators Inflamm. 2020 Feb 5;2020:6194864). The amino acid sequence of CXCL10 (Homo sapiens) is: MNQTAILICCLIFLTLSGIQGVPLSRTVRCTCISISNQPVNPRSLEKLEIIP15ASQFCPRVEIIATMKKKGEKRCLNPESKAIKNLLKAVSKERSKRSP (SEQ ID NO: 8) In some embodiments, an RNA polynucleotide disclosed herein can encode a CXCL10 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode a CXCL10 polypeptide wherein the CXCL10 polypeptide 20 comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 8. In some embodiments, an RNA polynucleotide disclosed herein can encode a CXCL10 polypeptide comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, an RNA polynucleotide disclosed herein can encode a CXCL10 polypeptide consisting of the25amino acid sequence of SEQ ID NO: 8. An RNA polynucleotide of the present disclosure can encode interferon beta 1 (IFNB1) and / or a variant of IFNB1. IFNB1 is a type I interferon cytokine that plays a key role in the innate immune response (see, e.g., Russell-Harde et al. Biochem Biophys Res Commun. 1999 Feb 16;255(2):539-44). The amino acid sequence of 30 IFNB1 (Homo sapiens) is: MTNKCLLQIALLLCFSTTALSMSYNLLGFLQRSSNFQCQKLLWQLNGRLEYC LKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWNETI VENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLKA KEYSHCAWTIVRVEILRNFYFINRLTGYLRN (SEQ ID NO: 9) 30 Attorney Docket No.07917-0454WO1 / UMMS 24-66 In some embodiments, an RNA polynucleotide disclosed herein can encode an IFNB1 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode an IFNB1 polypeptide wherein the IFNB1 polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, 5 or 99% identical to SEQ ID NO: 9. In some embodiments, an RNA polynucleotide disclosed herein can encode an IFNB1 polypeptide comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, an RNA polynucleotide disclosed herein can encode an IFNB1 polypeptide consisting of the amino acid sequence of SEQ ID NO: 9. 10 Provided herein is a composition comprising at least one RNA polynucleotide as disclosed herein encoding a cytokine polypeptide. In some embodiments, a composition disclosed herein is a “monotherapy” in that the composition comprises one RNA polynucleotide as disclosed herein encoding a cytokine or a tumor antigen polypeptide. In some embodiments, a composition disclosed herein is a 15 “monotherapy” in that the composition comprises more than one RNA polynucleotide as disclosed herein encoding a cytokine polypeptide, wherein the cytokine polypeptides are subunits, isoforms, variants, or precursors of the same cytokine. For example, a monotherapy can comprise an RNA polynucleotide encoding for an IL-18 isoform 1 polypeptide, an RNA polynucleotide encoding for an IL-18 isoform 2 20 polypeptide, or two RNA polynucleotides where one encodes for an IL-18 isoform 1 polypeptide and the other encodes for an IL-18 isoform 2 polypeptide. In some embodiments, a composition disclosed herein can comprise more than one RNA polynucleotide encoding a polypeptide. Compositions of the present disclosure that comprise more than one RNA polynucleotide encoding for more than 25 one polypeptide of interest can be referred to as a “cocktail” of RNA polynucleotides. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least about or about two, three, four, five, six, seven, eight, nine, ten, or more than ten RNA polynucleotides as disclosed herein. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least about or about two, three, four, 30 five, six, seven, eight, nine, ten, or more than ten RNA polynucleotides as disclosed herein wherein the RNA polynucleotides can encode for cytokine polypeptides, tumor antigen polypeptides, or both. 31 Attorney Docket No.07917-0454WO1 / UMMS 24-66 In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least about or about two, three, four, five, or six RNA polynucleotides encoding a cytokine polypeptide as disclosed herein. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least about or about 5 two, three, four, five, or six RNA polynucleotides encoding a cytokine polypeptide selected from the group of cytokine polypeptides consisting of IL-12, IL-15, IL-18, IFNB1, CXCL10, and CCL5. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise an RNA polynucleotide that encodes for IL-12 and at least about or about 10 one, two, three, four, or five additional RNA polynucleotides encoding a cytokine polypeptide as disclosed herein. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise an RNA polynucleotide that encodes for IL- 12 and at least about or about one, two, three, or four additional RNA polynucleotides encoding a cytokine polypeptide selected from the group of cytokine polypeptides 15 consisting of IL-18, IFNB1, CXCL10, and CCL5. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise an RNA polynucleotide that encodes for IL-12 and at least about or about one, two, three, four, or five additional RNA polynucleotides encoding a cytokine polypeptide selected from the group of cytokine polypeptides consisting of IL-15, IL-18, IFNB1, CXCL10, and 20 CCL5. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise five RNA polynucleotides that encode for the cytokine polypeptides IL-12, IL-18, IFNB1, CXCL10, and CCL5 (e.g., an RNA polynucleotide that encodes for IL- 12, an RNA polynucleotide that encodes for IL-18, an RNA polynucleotide that 25 encodes for IFNB1, an RNA polynucleotide that encodes for CXCL10, and an RNA polynucleotide that encodes for CCL5). In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise five RNA polynucleotides that encode for the cytokine polypeptides wherein the ratio of RNA polynucleotide that encodes for IL- 12: RNA polynucleotide that encodes for IL-18: RNA polynucleotide that encodes for 30 IFNB1: RNA polynucleotide that encodes for CXCL10: RNA polynucleotide that encodes for CCL5 is 1:1:1:1:1. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise about 10 μg to about 60 μg of an RNA polynucleotide that encodes for IL-12; about 10 μg to about 60 μg of an RNA polynucleotide that 32 Attorney Docket No.07917-0454WO1 / UMMS 24-66 encodes for IL-18; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for IFNB1; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for CXCL10; and about 10 μg to about 60 μg of an RNA polynucleotide that encodes for CCL5. In some embodiments, a composition (i.e., a cocktail) disclosed herein can 5 comprise about 10 μg of an RNA polynucleotide that encodes for IL-12; about 10 μg of an RNA polynucleotide that encodes for IL-18; about 10 μg of an RNA polynucleotide that encodes for IFNB1; about 10 μg of an RNA polynucleotide that encodes for CXCL10; and about 10 μg of an RNA polynucleotide that encodes for CCL5, wherein the total amount of RNA polynucleotides in the composition is about 10 50 μg. In some embodiments, a composition (i.e., a cocktail) disclosed herein, can comprise six RNA polynucleotides that encode for the cytokine polypeptides IL-12, IL-15, IL-18, IFNB1, CXCL10, and CCL5 (e.g., an RNA polynucleotide that encodes for IL-12, an RNA polynucleotide that encodes for IL-15, an RNA polynucleotide that 15 encodes for IL-18, an RNA polynucleotide that encodes for IFNB1, an RNA polynucleotide that encodes for CXCL10, and an RNA polynucleotide that encodes for CCL5). In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise six RNA polynucleotides that encode for the cytokine polypeptides wherein the ratio of RNA polynucleotide that encodes for IL-12: RNA polynucleotide 20 that encodes for IL-15: RNA polynucleotide that encodes for IL-18: RNA polynucleotide that encodes for IFNB1: RNA polynucleotide that encodes for CXCL10: RNA polynucleotide that encodes for CCL5 is 1:1:1:1:1:1. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise about 10 μg to about 60 μg of an RNA polynucleotide that encodes for IL-12; about 10 μg to 25 about 60 μg of an RNA polynucleotide that encodes for IL-15; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for IL-18; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for IFNB1; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for CXCL10; and about 10 μg to about 60 μg of an RNA polynucleotide that encodes for CCL5. In some embodiments, a composition 30 (i.e., a cocktail) disclosed herein can comprise about 10 μg of an RNA polynucleotide that encodes for IL-12; about 10 μg of an RNA polynucleotide that encodes for IL-15; about 10 μg of an RNA polynucleotide that encodes for IL-18; about 10 μg of an RNA polynucleotide that encodes for IFNB1; about 10 μg of of an RNA 33 Attorney Docket No.07917-0454WO1 / UMMS 24-66 polynucleotide that encodes for CXCL10; and about 10 μg of an RNA polynucleotide that encodes for CCL5, wherein the total amount of RNA polynucleotide in the composition is about 60 μg. Tumor Antigen Polypeptides 5 Tumor antigens as used herein refers to an antigen that is exclusively expressed or overexpressed in a tumor, preferably a solid tumor (e.g., PDAC). Based on the expression of the parental gene, tumor antigens can be classified into the general categories of tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) (see, e.g., Feola et al., Cancers (Basel). 2020 Jun 23;12(6):1660). In some 10 embodiments, an RNA polynucleotide disclosed herein can encode at least one tumor antigen polypeptide or variant thereof. An RNA polynucleotide of the present disclosure can encode mesothelin (MSLN) and / or a variant of MSLN. MSLN is a cell-surface antigen associated with tumor invasion, which is strongly expressed in many solid tumor types, including 15 mesothelioma, lung cancer, breast cancer, and pancreatic cancer (see, e.g., Morello et al., Cancer Discov. 2016;6:133–146). The amino acid sequence of MSLN (Homo sapiens) is: MALPTARPLLGSCGTPALGSLLFLLFSLGWVQPSRTLAGETGQEAAPLDGVL ANPPNISSLSPRQLLGFPCAEVSGLSTERVRELAVALAQKNVKLSTEQLRCL 20 AHRLSEPPEDLDALPLDLLLFLNPDAFSGPQACTRFFSRITKANVDLLPRGA PERQRLLPAALACWGVRGSLLSEADVRALGGLACDLPGRFVAESAEVLLPRL VSCPGPLDQDQQEAARAALQGGGPPYGPPSTWSVSTMDALRGLLPVLGQPII RSIPQGIVAAWRQRSSRDPSWRQPERTILRPRFRREVEKTACPSGKKAREID ESLIFYKKWELEACVDAALLATQMDRVNAIPFTYEQLDVLKHKLDELYPQGY 25 PESVIQHLGYLFLKMSPEDIRKWNVTSLETLKALLEVNKGHEMSPQAPRRPL PQVATLIDRFVKGRGQLDKDTLDTLTAFYPGYLCSLSPEELSSVPPSSIWAV RPQDLDTCDPRQLDVLYPKARLAFQNMNGSEYFVKIQSFLGGAPTEDLKALS QQNVSMDLATFMKLRTDAVLPLTVAEVQKLLGPHVEGLKAEERHRPVRDWIL RQRQDDLDTLGLGLQGGIPNGYLVLDLSMQEALSGTPCLLGPGPVLTVLALL30 LASTLA(SEQ ID NO: 10) In some embodiments, an RNA polynucleotide disclosed herein can encode a MSLN polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode a MSLN polypeptide wherein the MSLN polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99%35identical to SEQ ID NO: 10. In some embodiments, an RNA polynucleotide disclosed herein can encode a MSLN polypeptide comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, an RNA polynucleotide 34 Attorney Docket No.07917-0454WO1 / UMMS 24-66 disclosed herein can encode a MSLN polypeptide consisting of the amino acid sequence of SEQ ID NO: 10. An RNA polynucleotide of the present disclosure can encode mucin-1 (Muc1) and / or a variant of Muc1. Muc1 is a transmembrane glycoprotein that is aberrantly 5 glycosylated and overexpressed in a variety of epithelial cancers (see, e.g., Chen et al., Cancers (Basel). 2022 Dec 3;14(23):5983). The amino acid sequence of Muc1 (Homo sapiens) is: MTPGTQSPFFLLLLLTVLTVVTGSGHASSTPGGEKETSATQRSSVPSSTEKN AVSMTSSVLSSHSPGSGSSTTQGQDVTLAPATEPASGSAATWGQDVTSVPVT 10 RPALGSTTPPAHDVTSAPDNKPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAH GVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAP GSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTA PPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDT 15 RPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAH GVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAP GSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTA PPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDT 20 RPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAH GVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAP GSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTA PPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDT 25 RPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAH GVTSAPDNRPALGSTAPPVHNVTSASGSASGSASTLVHNGTSARATTTPASK STPFSIPSHHSDTPTTLASHSTKTDASSTHHSSVPPLTSSNHSTSPQLSTGV SFFFLSFHISNLQFNSSLEDPSTDYYQELQRDISEMFLQIYKQGGFLGLSNI KFRPGSVVVQLTLAFREGTINVHDVETQFNQYKTEAASRYNLTISDVSVSDV 30 PFPFSAQSGAGVPGWGIALLVLVCVLVALAIVYLIALAVCQCRRKNYGQLDI FPARDTYHPMSEYPTYHTHGRYVPPSSTDRSPYEKVSAGNGGSSLSYTNPAV AATSANL (SEQ ID NO: 11) In some embodiments, an RNA polynucleotide disclosed herein can encode a Muc1 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein 35 can encode a Muc1 polypeptide wherein the Muc1 polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 11. In some embodiments, an RNA polynucleotide disclosed herein can encode a Muc1 polypeptide comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, an RNA polynucleotide disclosed herein40can encode a Muc1 polypeptide consisting of the amino acid sequence of SEQ ID NO: 11. 35 Attorney Docket No.07917-0454WO1 / UMMS 24-66 An RNA polynucleotide of the present disclosure can encode prostate-specific membrane antigen (PSMA) and / or a variant of PSMA. PSMA is a type II integral membrane glycoprotein highly expressed in prostate cancer and is a tumor-associated antigen (TAA) (see, e.g., Chen et al., Cancers (Basel). 2022 Dec 3;14(23):5983). The 5 amino acid sequence of PSMA (Homo sapiens) is: MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNI TPKHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFG LDSVELAHYDVLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSD IVPPFSAFSPQGMPEGDLVYVNYARTEDFFKLERDMKINCSGKIVIARYGKV 10 FRGNKVKNAQLAGAKGVILYSDPADYFAPGVKSYPDGWNLPGGGVQRGNILN LNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGS APPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRG AVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTI LFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTP15LMYSLVHNLTKELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGND FEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETYELVEKFYDPMFKY HLTVAQVRGGMVFELANSIVLPFDCRDYAVVLRKYADKIYSISMKHPQEMKT YSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFI DPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVDPSKAWGEV 20 KRQIYVAAFTVQAAAETLSEVA (SEQ ID NO: 12) In some embodiments, an RNA polynucleotide disclosed herein can encode a PSMA polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode a PSMA polypeptide wherein the PSMA polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% 25 identical to SEQ ID NO: 12. In some embodiments, an RNA polynucleotide disclosed herein can encode a PSMA polypeptide comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, an RNA polynucleotide disclosed herein can encode a PSMA polypeptide consisting of the amino acid sequence of SEQ ID NO: 12.30An RNA polynucleotide of the present disclosure can encode epidermal growth factor receptor (EGFR) and / or a variant of EGFR. The amino acid sequence of EGFR (Homo sapiens) is: MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQ RMFNNCEVVLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENL35QIIRGNMYYENSYALAVLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPAL CNVESIQWRDIVSSDFLSNMSMDFQNHLGSCQKCDPSCPNGSCWGAGEENCQ KLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESDCLVCRKFRDEATC KDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSCVRACG ADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTS 40 ISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTD LHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKN 36 Attorney Docket No.07917-0454WO1 / UMMS 24-66 LCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEP RDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCT GRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNC TYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVRK 5 RTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYK GLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGI CLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRR LVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALE SILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQP 10 PICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMH LPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSA TSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEY INQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLNTVQP TCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAE15YLRVAPQSSEFIGA (SEQ ID NO: 13) In some embodiments, an RNA polynucleotide disclosed herein can encode an EGFR polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode an EGFR polypeptide wherein the EGFR polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% 20 identical to SEQ ID NO: 13. In some embodiments, an RNA polynucleotide disclosed herein can encode an EGFR polypeptide comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, an RNA polynucleotide disclosed herein can encode an EGFR polypeptide consisting of the amino acid sequence of SEQ ID NO: 13. 25 An RNA polynucleotide of the present disclosure can encode receptor tyrosine kinase like orphan receptor 1 (ROR1) and / or a variant of ROR1. The amino acid sequence of ROR1 (Homo sapiens) is: MHRPRRRGTRPPLLALLAALLLAARGAAAQETELSVSAELVPTSSWNISSEL NKDSYLTLDEPMNNITTSLGQTAELHCKVSGNPPPTIRWFKNDAPVVQEPRR 30 LSFRSTIYGSRLRIRNLDTTDTGYFQCVATNGKEVVSSTGVLFVKFGPPPTA SPGYSDEYEEDGFCQPYRGIACARFIGNRTVYMESLHMQGEIENQITAAFTM IGTSSHLSDKCSQFAIPSLCHYAFPYCDETSSVPKPRDLCRDECEILENVLC QTEYIFARSNPMILMRLKLPNCEDLPQPESPEAANCIRIGIPMADPINKNHK CYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFPELNGGHSYCRN35PGNQKEAPWCFTLDENFKSDLCDIPACDSKDSKEKNKMEILYILVPSVAIPL AIALLFFFICVCRNNQKSSSAPVQRQPKHVRGQNVEMSMLNAYKPKSKAKEL PLSAVRFMEELGECAFGKIYKGHLYLPGMDHAQLVAIKTLKDYNNPQQWTEF QQEASLMAELHHPNIVCLLGAVTQEQPVCMLFEYINQGDLHEFLIMRSPHSD VGCSSDEDGTVKSSLDHGDFLHIAIQIAAGMEYLSSHFFVHKDLAARNILIG 40 EQLHVKISDLGLSREIYSADYYRVQSKSLLPIRWMPPEAIMYGKFSSDSDIW SFGVVLWEIFSFGLQPYYGFSNQEVIEMVRKRQLLPCSEDCPPRMYSLMTEC WNEIPSRRPRFKDIHVRLRSWEGLSSHTSSTTPSGGNATTQTTSLSASPVSN LSNPRYPNYMFPSQGITPQGQIAGFIGPPIPQNQRFIPINGYPIPPGYAAFP AAHYQPTGPPRVIQHCPPPKSRSPSSASGSTSTGHVTSLPSSGSNQEANIPL 37 Attorney Docket No.07917-0454WO1 / UMMS 24-66 LPHMSIPNHPGGMGITVFGNKSQKPYKIDSKQASLLGDANIHGHTESMISAE L (SEQ ID NO: 14) In some embodiments, an RNA polynucleotide disclosed herein can encode an ROR1 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein 5 can encode an ROR1 polypeptide wherein the ROR1 polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 14. In some embodiments, an RNA polynucleotide disclosed herein can encode an ROR1 polypeptide comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, an RNA polynucleotide 10 disclosed herein can encode an ROR1 polypeptide consisting of the amino acid sequence of SEQ ID NO: 14. An RNA polynucleotide of the present disclosure can encode transferrin (TR) and / or a variant of TR. The amino acid sequence of TR (Homo sapiens) is: MRLAVGALLVCAVLGLCLAVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSD 15 GPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFY GSKEDPQTFYYAVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYC DLPEPRKPLEKAVANFFSGSCAPCADGTDFPQLCQLCPGCGCSTLNQYFGYS GAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLCLDNTRKPVDEYKDC HLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGKDL 20 LFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWC ALSHHERLKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVY IAGKCGLVPVLAENYNKSDNCEDTPEAGYFAVAVVKKSASDLTWDNLKGKKS CHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEGCAPGSKKDSSLCKLCMGS GLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNPDPWAKN25LNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQ HLFGSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVK AVGNLRKCSTSSLLEACTFRRP (SEQ ID NO: 15) In some embodiments, an RNA polynucleotide disclosed herein can encode a TR polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can30encode a TR polypeptide wherein the TR polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 15. In some embodiments, an RNA polynucleotide disclosed herein can encode a TR polypeptide comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, an RNA polynucleotide disclosed herein can 35 encode a TR polypeptide consisting of the amino acid sequence of SEQ ID NO: 15. An RNA polynucleotide of the present disclosure can encode carcinoembryonic antigen (CEA) and / or a variant of CEA. The amino acid sequence of CEA (Homo sapiens) is: 38 Attorney Docket No.07917-0454WO1 / UMMS 24-66 MESPSAPPHRWCIPWQRLLLTGEGRTTWERVGGGSWGLLGRTGL (SEQ ID NO: 16) In some embodiments, an RNA polynucleotide disclosed herein can encode a CEA polypeptide. In some embodiments, an RNA polynucleotide disclosed herein 5 can encode a CEA polypeptide wherein the CEA polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 16. In some embodiments, an RNA polynucleotide disclosed herein can encode a CEA polypeptide comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, an RNA polynucleotide disclosed herein 10 can encode a CEA polypeptide consisting of the amino acid sequence of SEQ ID NO: 16. An RNA polynucleotide of the present disclosure can encode tyrosine kinase- type cell surface receptor HER2 (HER2), an isoform, and / or a variant of HER2. The amino acid sequence of HER2 (Homo sapiens) is:15MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQG CQVVQGNLELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRG TQLFEDNYALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQ RNPQLCYQDTILWKDIFHKNNQLALTLIDTNRSRACHPCSPMCKGSRCWGES SEDCQSLTRTVCAGGCARCKGPLPTDCCHEQCAAGCTGPKHSDCLACLHFNH 20 SGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACPYNYLSTDVGSCT LVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSANIQEF AGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWP DSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALI HHNTHLCFVHTVPWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHC 25 WGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQNG SVTCFGPEADQCVACAHYKDPPFCVARCPSGVKPDLSYMPIWKFPDEEGACQ PCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVGILLVVVLGVVFGILIK RRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETELRKVKVLGS GAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSP30YVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKG MSYLEDVRLVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKV PIKWMALESILRRRFTHQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLE KGERLPQPPICTIDVYMIMVKCWMIDSECRPRFRELVSEFSRMARDPQRFVV IQNEDLGPASPLDSTFYRSLLEDDDMGDLVDAEEYLVPQQGFFCPDPAPGAG 35 GMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEGAGSDVFDGDLGM GAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYVNQPD VRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEY LTPQGGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEY LGLDVPV (SEQ ID NO: 17) 40 In some embodiments, an RNA polynucleotide disclosed herein can encode a HER2 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode a HER2 polypeptide wherein the HER2 polypeptide comprises an amino 39 Attorney Docket No.07917-0454WO1 / UMMS 24-66 acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 17. In some embodiments, an RNA polynucleotide disclosed herein can encode a HER2 polypeptide comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, an RNA polynucleotide disclosed herein 5 can encode a HER2 polypeptide consisting of the amino acid sequence of SEQ ID NO: 17. An RNA polynucleotide of the present disclosure can encode tumor-associated calcium signal transducer 2 (TROP2) and / or a variant of TROP2. The amino acid sequence of TROP2 (Homo sapiens) is: 10 MARGPGLAPPPLRLPLLLLVLAAVTGHTAAQDNCTCPTNKMTVCSPDGPGGR CQCRALGSGMAVDCSTLTSKCLLLKARMSAPKNARTLVRPSEHALVDNDGLY DPDCDPEGRFKARQCNQTSVCWCVNSVGVRRTDKGDLSLRCDELVRTHHILI DLRHRPTAGAFNHSDLDAELRRLFRERYRLHPKFVAAVHYEQPTIQIELRQN TSQKAAGDVDIGDAAYYFERDIKGESLFQGRGGLDLRVRGEPLQVERTLIYY15LDEIPPKFSMKRLTAGLIAVIVVVVVALVAGMAVLVITNRRKSGKYKKVEIK ELGELRKEPSL (SEQ ID NO: 18) In some embodiments, an RNA polynucleotide disclosed herein can encode a TROP2 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode a TROP2 polypeptide wherein the TROP2 polypeptide comprises an20amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 18. In some embodiments, an RNA polynucleotide disclosed herein can encode a TROP2 polypeptide comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, an RNA polynucleotide disclosed herein can encode a TROP2 polypeptide consisting of the amino acid 25 sequence of SEQ ID NO: 18. An RNA polynucleotide of the present disclosure can encode claudin 18.2 (CLDN18.2), an isoform, and / or a variant of CLDN18.2. The amino acid sequence of CLDN18.2 (Homo sapiens) is: MAVTACQGLGFVVSLIGIAGIIAATCMDQWSTQDLYNNPVTAVFNYQGLWRS 30 CVRESSGFTECRGYFTLLGLPAMLQAVRALMIVGIVLGAIGLLVSIFALKCI RIGSMEDSAKANMTLTSGIMFIVSGLCAIAGVSVFANMLVTNFWMSTANMYT GMGGMVQTVQTRYTFGAALFVGWVAGGLTLIGGVMMCIACRGLAPEETNYKA VSYHASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSKHDY V (SEQ ID NO: 19) 35 In some embodiments, an RNA polynucleotide disclosed herein can encode a CLDN18.2 polypeptide. In some embodiments, an RNA polynucleotide disclosed 40 Attorney Docket No.07917-0454WO1 / UMMS 24-66 herein can encode a CLDN18.2 polypeptide wherein the CLDN18.2 polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 19. In some embodiments, an RNA polynucleotide disclosed herein can encode a CLDN18.2 polypeptide 5 comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, an RNA polynucleotide disclosed herein can encode a CLDN18.2 polypeptide consisting of the amino acid sequence of SEQ ID NO: 19. An RNA polynucleotide of the present disclosure can encode mucin-16 (Muc16), an isoform, and / or a variant of Muc16. The amino acid sequence of Muc16 10 (Homo sapiens) is: MLKPSGLPGSSSPTRSLMTGSRSTKATPEMDSGLTGATLSPKTSTGAIVVTE HTLPFTSPDKTLASPTSSVVGRTTQSLGVMSSALPESTSRGMTHSEQRTSPS LSPQVNGTPSRNYPATSMVSGLSSPRTRTSSTEGNFTKEASTYTLTVETTSG PVTEKYTVPTETSTTEGDSTETPWDTRYIPVKITSPMKTFADSTASKENAPV 15 SMTPAETTVTDSHTPGRTNPSFGTLYSSFLDLSPKGTPNSRGETSLELILST TGYPFSSPEPGSAGHSRISTSAPLSSSASVLDNKISETSIFSGQSLTSPLSP GVPEARASTMPNSAIPFSMTLSNAETSAERVRSTISSLGTPSISTKQTAETI LTFHAFAETMDIPSTHIAKTLASEWLGSPGTLGGTSTSALTTTSPSTTLVSE ETNTHHSTSGKETEGTLNTSMTPLETSAPGEESEMTATLVPTLGFTTLDSKI 20 RSPSQVSSSHPTRELRTTGSTSGRQSSSTAAHGSSDILRATTSSTSKASSWT SESTAQQFSEPQHTQWVETSPSMKTERPPASTSVAAPITTSVPSVVSGFTTL KTSSTKGIWLEETSADTLIGESTAGPTTHQFAVPTGISMTGGSSTRGSQGTT HLLTRATASSETSADLTLATNGVPVSVSPAVSKTAAGSSPPGGTKPSYTMVS SVIPETSSLQSSAFREGTSLGLTPLNTRHPFSSPEPDSAGHTKISTSIPLLS 25 SASVLEDKVSATSTFSHHKATSSITTGTPEISTKTKPSSAVLSSMTLSNAAT SPERVRNATSPLTHPSPSGEETAGSVLTLSTSAETTDSPNIHPTGTLTSESS ESPSTLSLPSVSGVKTTFSSSTPSTHLFTSGEETEETSNPSVSQPETSVSRV RTTLASTSVPTPVFPTMDTWPTRSAQFSSSHLVSELRATSSTSVTNSTGSAL PKISHLTGTATMSQTNRDTFNDSAAPQSTTWPETSPRFKTGLPSATTTVSTS 30 ATSLSATVMVSKFTSPATSSMEATSIREPSTTILTTETTNGPGSMAVASTNI PIGKGYITEGRLDTSHLPIGTTASSETSMDFTMAKESVSMSVSPSQSMDAAG SSTPGRTSQFVDTFSDDVYHLTSREITIPRDGTSSALTPQMTATHPPSPDPG SARSTWLGILSSSPSSPTPKVTMSSTFSTQRVTTSMIMDTVETSRWNMPNLP STTSLTPSNIPTSGAIGKSTLVPLDTPSPATSLEASEGGLPTLSTYPESTNT 35 PSIHLGAHASSESPSTIKLTMASVVKPGSYTPLTFPSIETHIHVSTARMAYS SGSSPEMTAPGETNTGSTWDPTTYITTTDPKDTSSAQVSTPHSVRTLRTTEN HPKTESATPAAYSGSPKISSSPNLTSPATKAWTITDTTEHSTQLHYTKLAEK SSGFETQSAPGPVSVVIPTSPTIGSSTLELTSDVPGEPLVLAPSEQTTITLP MATWLSTSLTEEMASTDLDISSPSSPMSTFAIFPPMSTPSHELSKSEADTSA 40 IRNTDSTTLDQHLGIRSLGRTGDLTTVPITPLTTTWTSVIEHSTQAQDTLSA TMSPTHVTQSLKDQTSIPASASPSHLTEVYPELGTQGRSSSEATTFWKPSTD TLSREIETGPTNIQSTPPMDNTTTGSSSSGVTLGIAHLPIGTSSPAETSTNM ALERRSSTATVSMAGTMGLLVTSAPGRSISQSLGRVSSVLSESTTEGVTDSS KGSSPRLNTQGNTALSSSLEPSYAEGSQMSTSIPLTSSPTTPDVEFIGGSTF45WTKEVTTVMTSDISKSSARTESSSATLMSTALGSTENTGKEKLRTASMDLPS PTPSMEVTPWISLTLSNAPNTTDSLDLSHGVHTSSAGTLATDRSLNTGVTRA SRLENGSDTSSKSLSMGNSTHTSMTYTEKSEVSSSIHPRPETSAPGAETTLT STPGNRAISLTLPFSSIPVEEVISTGITSGPDINSAPMTHSPITPPTIVWTS 41 Attorney Docket No.07917-0454WO1 / UMMS 24-66 TGTIEQSTQPLHAVSSEKVSVQTQSTPYVNSVAVSASPTHENSVSSGSSTSS PYSSASLESLDSTISRRNAITSWLWDLTTSLPTTTWPSTSLSEALSSGHSGV SNPSSTTTEFPLFSAASTSAAKQRNPETETHGPQNTAASTLNTDASSVTGLS ETPVGASISSEVPLPMAITSRSDVSGLTSESTANPSLGTASSAGTKLTRTIS 5 LPTSESLVSFRMNKDPWTVSIPLGSHPTTNTETSIPVNSAGPPGLSTVASDV IDTPSDGAESIPTVSFSPSPDTEVTTISHFPEKTTHSFRTISSLTHELTSRV TPIPGDWMSSAMSTKPTGASPSITLGERRTITSAAPTTSPIVLTASFTETST VSLDNETTVKTSDILDARKTNELPSDSSSSSDLINTSIASSTMDVTKTASIS PTSISGMTASSSPSLFSSDRPQVPTSTTETNTATSPSVSSNTYSLDGGSNVG 10 GTPSTLPPFTITHPVETSSALLAWSRPVRTFSTMVSTDTASGENPTSSNSVV TSVPAPGTWTSVGSTTDLPAMGFLKTSPAGEAHSLLASTIEPATAFTPHLSA AVVTGSSATSEASLLTTSESKAIHSSPQTPTTPTSGANWETSATPESLLVVT ETSDTTLTSKILVTDTILFSTVSTPPSKFPSTGTLSGASFPTLLPDTPAIPL TATEPTSSLATSFDSTPLVTIASDSLGTVPETTLTMSETSNGDALVLKTVSN 15 PDRSIPGITIQGVTESPLHPSSTSPSKIVAPRNTTYEGSITVALSTLPAGTT GSLVFSQSSENSETTALVDSSAGLERASVMPLTTGSQGMASSGGIRSGSTHS TGTKTFSSLPLTMNPGEVTAMSEITTNRLTATQSTAPKGIPVKPTSAESGLL TPVSASSSPSKAFASLTTAPPTWGIPQSTLTFEFSEVPSLDTKSASLPTPGQ SLNTIPDSDASTASSSLSKSPEKNPRARMMTSTKAISASSFQSTGFTETPEG 20 SASPSMAGHEPRVPTSGTGDPRYASESMSYPDPSKASSAMTSTSLASKLTTL FSTGQAARSGSSSSPISLSTEKETSFLSPTASTSRKTSLFLGPSMARQPNIL VHLQTSALTLSPTSTLNMSQEEPPELTSSQTIAEEEGTTAETQTLTFTPSET PTSLLPVSSPTEPTARRKSSPETWASSISVPAKTSLVETTDGTLVTTIKMSS QAAQGNSTWPAPAEETGSSPAGTSPGSPEMSTTLKIMSSKEPSISPEIRSTV 25 RNSPWKTPETTVPMETTVEPVTLQSTALGSGSTSISHLPTGTTSPTKSPTEN MLATERVSLSPSPPEAWTNLYSGTPGGTRQSLATMSSVSLESPTARSITGTG QQSSPELVSKTTGMEFSMWHGSTGGTTGDTHVSLSTSSNILEDPVTSPNSVS SLTDKSKHKTETWVSTTAIPSTVLNNKIMAAEQQTSRSVDEAYSSTSSWSDQ TSGSDITLGASPDVTNTLYITSTAQTTSLVSLPSGDQGITSLTNPSGGKTSS 30 ASSVTSPSIGLETLRANVSAVKSDIAPTAGHLSQTSSPAEVSILDVTTAPTP GISTTITTMGTNSISTTTPNPEVGMSTMDSTPATERRTTSTEHPSTWSSTAA SDSWTVTDMTSNLKVARSPGTISTMHTTSFLASSTELDSMSTPHGRITVIGT SLVTPSSDASAVKTETSTSERTLSPSDTTASTPISTFSRVQRMSISVPDILS TSWTPSSTEAEDVPVSMVSTDHASTKTDPNTPLSTFLFDSLSTLDWDTGRSL35SSATATTSAPQGATTPQELTLETMISPATSQLPFSIGHITSAVTPAAMARSS GVTFSRPDPTSKKAEQTSTQLPTTTSAHPGQVPRSAATTLDVIPHTAKTPDA TFQRQGQTALTTEARATSDSWNEKEKSTPSAPWITEMMNSVSEDTIKEVTSS SSVLRTLNTLDINLESGTTSSPSWKSSPYERIAPSESTTDKEAIHPSTNTVE TTGWVTSSEHASHSTIPAHSASSKLTSPVVTTSTREQAIVSMSTTTWPESTR 40 ARTEPNSFLTIELRDVSPYMDTSSTTQTSIISSPGSTAITKGPRTEITSSKR ISSSFLAQSMRSSDSPSEAITRLSNFPAMTESGGMILAMQTSPPGATSLSAP TLDTSATASWTGTPLATTQRFTYSEKTTLFSKGPEDTSQPSPPSVEETSSSS SLVPIHATTSPSNILLTSQGHSPSSTPPVTSVFLSETSGLGKTTDMSRISLE PGTSLPPNLSSTAGEALSTYEASRDTKAIHHSADTAVTNMEATSSEYSPIPG 45 HTKPSKATSPLVTSHIMGDITSSTSVFGSSETTEIETVSSVNQGLQERSTSQ VASSATETSTVITHVSSGDATTHVTKTQATFSSGTSISSPHQFITSTNTFTD VSTNPSTSLIMTESSGVTITTQTGPTGAATQGPYLLDTSTMPYLTETPLAVT PDFMQSEKTTLISKGPKDVSWTSPPSVAETSYPSSLTPFLVTTIPPATSTLQ GQHTSSPVSATSVLTSGLVKTTDMLNTSMEPVTNSPQNLNNPSNEILATLAA50TTDIETIHPSINKAVTNMGTASSAHVLHSTLPVSSEPSTATSPMVPASSMGD ALASISIPGSETTDIEGEPTSSLTAGRKENSTLQEMNSTTESNIILSNVSVG AITEATKMEVPSFDATFIPTPAQSTKFPDIFSVASSRLSNSPPMTISTHMTT TQTGSSGATSKIPLALDTSTLETSAGTPSVVTEGFAHSKITTAMNNDVKDVS QTNPPFQDEASSPSSQAPVLVTTLPSSVAFTPQWHSTSSPVSMSSVLTSSLV 55 KTAGKVDTSLETVTSSPQSMSNTLDDISVTSAATTDIETTHPSINTVVTNVG 42 Attorney Docket No.07917-0454WO1 / UMMS 24-66 TTGSAFESHSTVSAYPEPSKVTSPNVTTSTMEDTTISRSIPKSSKTTRTETE TTSSLTPKLRETSISQEITSSTETSTVPYKELTGATTEVSRTDVTSSSSTSF PGPDQSTVSLDISTETNTRLSTSPIMTESAEITITTQTGPHGATSQDTFTMD PSNTTPQAGIHSAMTHGFSQLDVTTLMSRIPQDVSWTSPPSVDKTSSPSSFL 5 SSPAMTTPSLISSTLPEDKLSSPMTSLLTSGLVKITDILRTRLEPVTSSLPN FSSTSDKILATSKDSKDTKEIFPSINTEETNVKANNSGHESHSPALADSETP KATTQMVITTTVGDPAPSTSMPVHGSSETTNIKREPTYFLTPRLRETSTSQE SSFPTDTSFLLSKVPTGTITEVSSTGVNSSSKISTPDHDKSTVPPDTFTGEI PRVFTSSIKTKSAEMTITTQASPPESASHSTLPLDTSTTLSQGGTHSTVTQG 10 FPYSEVTTLMGMGPGNVSWMTTPPVEETSSVSSLMSSPAMTSPSPVSSTSPQ SIPSSPLPVTALPTSVLVTTTDVLGTTSPESVTSSPPNLSSITHERPATYKD TAHTEAAMHHSTNTAVTNVGTSGSGHKSQSSVLADSETSKATPLMSTTSTLG DTSVSTSTPNISQTNQIQTEPTASLSPRLRESSTSEKTSSTTETNTAFSYVP TGAITQASRTEISSSRTSISDLDRPTIAPDISTGMITRLFTSPIMTKSAEMT 15 VTTQTTTPGATSQGILPWDTSTTLFQGGTHSTVSQGFPHSEITTLRSRTPGD VSWMTTPPVEETSSGFSLMSPSMTSPSPVSSTSPESIPSSPLPVTALLTSVL VTTTNVLGTTSPEPVTSSPPNLSSPTQERLTTYKDTAHTEAMHASMHTNTAV ANVGTSISGHESQSSVPADSHTSKATSPMGITFAMGDTSVSTSTPAFFETRI QTESTSSLIPGLRDTRTSEEINTVTETSTVLSEVPTTTTTEVSRTEVITSSR 20 TTISGPDHSKMSPYISTETITRLSTFPFVTGSTEMAITNQTGPIGTISQATL TLDTSSTASWEGTHSPVTQRFPHSEETTTMSRSTKGVSWQSPPSVEETSSPS SPVPLPAITSHSSLYSAVSGSSPTSALPVTSLLTSGRRKTIDMLDTHSELVT SSLPSASSFSGEILTSEASTNTETIHFSENTAETNMGTTNSMHKLHSSVSIH SQPSGHTPPKVTGSMMEDAIVSTSTPGSPETKNVDRDSTSPLTPELKEDSTA 25 LVMNSTTESNTVFSSVSLDAATEVSRAEVTYYDPTFMPASAQSTKSPDISPE ASSSHSNSPPLTISTHKTIATQTGPSGVTSLGQLTLDTSTIATSAGTPSART QDFVDSETTSVMNNDLNDVLKTSPFSAEEANSLSSQAPLLVTTSPSPVTSTL QEHSTSSLVSVTSVPTPTLAKITDMDTNLEPVTRSPQNLRNTLATSEATTDT HTMHPSINTAVANVGTTSSPNEFYFTVSPDSDPYKATSAVVITSTSGDSIVS 30 TSMPRSSAMKKIESETTFSLIFRLRETSTSQKIGSSSDTSTVFDKAFTAATT EVSRTELTSSSRTSIQGTEKPTMSPDTSTRSVTMLSTFAGLTKSEERTIATQ TGPHRATSQGTLTWDTSITTSQAGTHSAMTHGFSQLDLSTLTSRVPEYISGT SPPSVEKTSSSSSLLSLPAITSPSPVPTTLPESRPSSPVHLTSLPTSGLVKT TDMLASVASLPPNLGSTSHKIPTTSEDIKDTEKMYPSTNIAVTNVGTTTSEK35ESYSSVPAYSEPPKVTSPMVTSFNIRDTIVSTSMPGSSEITRIEMESTFSLA HGLKGTSTSQDPIVSTEKSAVLHKLTTGATETSRTEVASSRRTSIPGPDHST ESPDISTEVIPSLPISLGITESSNMTIITRTGPPLGSTSQGTFTLDTPTTSS RAGTHSMATQEFPHSEMTTVMNKDPEILSWTIPPSIEKTSFSSSLMPSPAMT SPPVSSTLPKTIHTTPSPMTSLLTPSLVMTTDTLGTSPEPTTSSPPNLSSTS 40 HEILTTDEDTTAIEAMHPSTSTAATNVETTSSGHGSQSSVLADSEKTKATAP MDTTSTMGHTTVSTSMSVSSETTKIKRESTYSLTPGLRETSISQNASFSTDT SIVLSEVPTGTTAEVSRTEVTSSGRTSIPGPSQSTVLPEISTRTMTRLFASP TMTESAEMTIPTQTGPSGSTSQDTLTLDTSTTKSQAKTHSTLTQRFPHSEMT TLMSRGPGDMSWQSSPSLENPSSLPSLLSLPATTSPPPISSTLPVTISSSPL 45 PVTSLLTSSPVTTTDMLHTSPELVTSSPPKLSHTSDERLTTGKDTTNTEAVH PSTNTAASNVEIPSSGHESPSSALADSETSKATSPMFITSTQEDTTVAISTP HFLETSRIQKESISSLSPKLRETGSSVETSSAIETSAVLSEVSIGATTEISR TEVTSSSRTSISGSAESTMLPEISTTRKIIKFPTSPILAESSEMTIKTQTSP PGSTSESTFTLDTSTTPSLVITHSTMTQRLPHSEITTLVSRGAGDVPRPSSL50PVEETSPPSSQLSLSAMISPSPVSSTLPASSHSSSASVTSLLTPGQVKTTEV LDASAEPETSSPPSLSSTSVEILATSEVTTDTEKIHPFSNTAVTKVGTSSSG HESPSSVLPDSETTKATSAMGTISIMGDTSVSTLTPALSNTRKIQSEPASSL TTRLRETSTSEETSLATEANTVLSKVSTGATTEVSRTEAISFSRTSMSGPEQ STMSQDISIGTIPRISASSVLTESAKMTITTQTGPSESTLESTLNLNTATTP 55 SWVETHSIVIQGFPHPEMTTSMGRGPGGVSWPSPPFVKETSPPSSPLSLPAV 43 Attorney Docket No.07917-0454WO1 / UMMS 24-66 TSPHPVSTTFLAHIPPSPLPVTSLLTSGPATTTDILGTSTEPGTSSSSSLST TSHERLTTYKDTAHTEAVHPSTNTGGTNVATTSSGYKSQSSVLADSSPMCTT STMGDTSVLTSTPAFLETRRIQTELASSLTPGLRESSGSEGTSSGTKMSTVL SKVPTGATTEISKEDVTSIPGPAQSTISPDISTRTVSWFSTSPVMTESAEIT 5 MNTHTSPLGATTQGTSTLDTSSTTSLTMTHSTISQGFSHSQMSTLMRRGPED VSWMSPPLLEKTRPSFSLMSSPATTSPSPVSSTLPESISSSPLPVTSLLTSG LAKTTDMLHKSSEPVTNSPANLSSTSVEILATSEVTTDTEKTHPSSNRTVTD VGTSSSGHESTSFVLADSQTSKVTSPMVITSTMEDTSVSTSTPGFFETSRIQ TEPTSSLTLGLRKTSSSEGTSLATEMSTVLSGVPTGATAEVSRTEVTSSSRT 10 SISGFAQLTVSPETSTETITRLPTSSIMTESAEMMIKTQTDPPGSTPESTHT VDISTTPNWVETHSTVTQRFSHSEMTTLVSRSPGDMLWPSQSSVEETSSASS LLSLPATTSPSPVSSTLVEDFPSASLPVTSLLNPGLVITTDRMGISREPGTS STSNLSSTSHERLTTLEDTVDTEDMQPSTHTAVTNVRTSISGHESQSSVLSD SETPKATSPMGTTYTMGETSVSISTSDFFETSRIQIEPTSSLTSGLRETSSS 15 ERISSATEGSTVLSEVPSGATTEVSRTEVISSRGTSMSGPDQFTISPDISTE AITRLSTSPIMTESAESAITIETGSPGATSEGTLTLDTSTTTFWSGTHSTAS PGFSHSEMTTLMSRTPGDVPWPSLPSVEEASSVSSSLSSPAMTSTSFFSTLP ESISSSPHPVTALLTLGPVKTTDMLRTSSEPETSSPPNLSSTSAEILATSEV TKDREKIHPSSNTPVVNVGTVIYKHLSPSSVLADLVTTKPTSPMATTSTLGN 20 TSVSTSTPAFPETMMTQPTSSLTSGLREISTSQETSSATERSASLSGMPTGA TTKVSRTEALSLGRTSTPGPAQSTISPEISTETITRISTPLTTTGSAEMTIT PKTGHSGASSQGTFTLDTSSRASWPGTHSAATHRSPHSGMTTPMSRGPEDVS WPSRPSVEKTSPPSSLVSLSAVTSPSPLYSTPSESSHSSPLRVTSLFTPVMM KTTDMLDTSLEPVTTSPPSMNITSDESLATSKATMETEAIQLSENTAVTQMG 25 TISARQEFYSSYPGLPEPSKVTSPVVTSSTIKDIVSTTIPASSEITRIEMES TSTLTPTPRETSTSQEIHSATKPSTVPYKALTSATIEDSMTQVMSSSRGPSP DQSTMSQDISTEVITRLSTSPIKTESTEMTITTQTGSPGATSRGTLTLDTST TFMSGTHSTASQGFSHSQMTALMSRTPGDVPWLSHPSVEEASSASFSLSSPV MTSSSPVSSTLPDSIHSSSLPVTSLLTSGLVKTTELLGTSSEPETSSPPNLS 30 STSAEILAITEVTTDTEKLEMTNVVTSGYTHESPSSVLADSVTTKATSSMGI TYPTGDTNVLTSTPAFSDTSRIQTKSKLSLTPGLMETSISEETSSATEKSTV LSSVPTGATTEVSRTEAISSSRTSIPGPAQSTMSSDTSMETITRISTPLTRK ESTDMAITPKTGPSGATSQGTFTLDSSSTASWPGTHSATTQRFPQSVVTTPM SRGPEDVSWPSPLSVEKNSPPSSLVSSSSVTSPSPLYSTPSGSSHSSPVPVT35SLFTSIMMKATDMLDASLEPETTSAPNMNITSDESLAASKATTETEAIHVFE NTAASHVETTSATEELYSSSPGFSEPTKVISPVVTSSSIRDNMVSTTMPGSS GITRIEIESMSSLTPGLRETRTSQDITSSTETSTVLYKMPSGATPEVSRTEV MPSSRTSIPGPAQSTMSLDISDEVVTRLSTSPIMTESAEITITTQTGYSLAT SQVTLPLGTSMTFLSGTHSTMSQGLSHSEMTNLMSRGPESLSWTSPRFVETT 40 RSSSSLTSLPLTTSLSPVSSTLLDSSPSSPLPVTSLILPGLVKTTEVLDTSS EPKTSSSPNLSSTSVEIPATSEIMTDTEKIHPSSNTAVAKVRTSSSVHESHS SVLADSETTITIPSMGITSAVDDTTVFTSNPAFSETRRIPTEPTFSLTPGFR ETSTSEETTSITETSAVLYGVPTSATTEVSMTEIMSSNRIHIPDSDQSTMSP DIITEVITRLSSSSMMSESTQMTITTQKSSPGATAQSTLTLATTTAPLARTH 45 STVPPRFLHSEMTTLMSRSPENPSWKSSLFVEKTSSSSSLLSLPVTTSPSVS STLPQSIPSSSFSVTSLLTPGMVKTTDTSTEPGTSLSPNLSGTSVEILAASE VTTDTEKIHPSSSMAVTNVGTTSSGHELYSSVSIHSEPSKATYPVGTPSSMA ETSISTSMPANFETTGFEAEPFSHLTSGFRKTNMSLDTSSVTPTNTPSSPGS THLLQSSKTDFTSSAKTSSPDWPPASQYTEIPVDIITPFNASPSITESTGIT50SFPESRFTMSVTESTHHLSTDLLPSAETISTGTVMPSLSEAMTSFATTGVPR AISGSGSPFSRTESGPGDATLSTIAESLPSSTPVPFSSSTFTTTDSSTIPAL HEITSSSATPYRVDTSLGTESSTTEGRLVMVSTLDTSSQPGRTSSSPILDTR MTESVELGTVTSAYQVPSLSTRLTRTDGIMEHITKIPNEAAHRGTIRPVKGP QTSTSPASPKGLHTGGTKRMETTTTALKTTTTALKTTSRATLTTSVYTPTLG 55 TLTPLNASMQMASTIPTEMMITTPYVFPDVPETTSSLATSLGAETSTALPRT 44 Attorney Docket No.07917-0454WO1 / UMMS 24-66 TPSVFNRESETTASLVSRSGAERSPVIQTLDVSSSEPDTTASWVIHPAETIP TVSKTTPNFFHSELDTVSSTATSHGADVSSAIPTNISPSELDALTPLVTISG TDTSTTFPTLTKSPHETETRTTWLTHPAETSSTIPRTIPNFSHHESDATPSI ATSPGAETSSAIPIMTVSPGAEDLVTSQVTSSGTDRNMTIPTLTLSPGEPKT 5 IASLVTHPEAQTSSAIPTSTISPAVSRLVTSMVTSLAAKTSTTNRALTNSPG EPATTVSLVTHPAQTSPTVPWTTSIFFHSKSDTTPSMTTSHGAESSSAVPTP TVSTEVPGVVTPLVTSSRAVISTTIPILTLSPGEPETTPSMATSHGEEASSA IPTPTVSPGVPGVVTSLVTSSRAVTSTTIPILTFSLGEPETTPSMATSHGTE AGSAVPTVLPEVPGMVTSLVASSRAVTSTTLPTLTLSPGEPETTPSMATSHG 10 AEASSTVPTVSPEVPGVVTSLVTSSSGVNSTSIPTLILSPGELETTPSMATS HGAEASSAVPTPTVSPGVSGVVTPLVTSSRAVTSTTIPILTLSSSEPETTPS MATSHGVEASSAVLTVSPEVPGMVTSLVTSSRAVTSTTIPTLTISSDEPETT TSLVTHSEAKMISAIPTLAVSPTVQGLVTSLVTSSGSETSAFSNLTVASSQP ETIDSWVAHPGTEASSVVPTLTVSTGEPFTNISLVTHPAESSSTLPRTTSRF 15 SHSELDTMPSTVTSPEAESSSAISTTISPGIPGVLTSLVTSSGRDISATFPT VPESPHESEATASWVTHPAVTSTTVPRTTPNYSHSEPDTTPSIATSPGAEAT SDFPTITVSPDVPDMVTSQVTSSGTDTSITIPTLTLSSGEPETTTSFITYSE THTSSAIPTLPVSPGASKMLTSLVISSGTDSTTTFPTLTETPYEPETTAIQL IHPAETNTMVPRTTPKFSHSKSDTTLPVAITSPGPEASSAVSTTTISPDMSD 20 LVTSLVPSSGTDTSTTFPTLSETPYEPETTATWLTHPAETSTTVSGTIPNFS HRGSDTAPSMVTSPGVDTRSGVPTTTIPPSIPGVVTSQVTSSATDTSTAIPT LTPSPGEPETTASSATHPGTQTGFTVPIRTVPSSEPDTMASWVTHPPQTSTP VSRTTSSFSHSSPDATPVMATSPRTEASSAVLTTISPGAPEMVTSQITSSGA ATSTTVPTLTHSPGMPETTALLSTHPRTETSKTFPASTVFPQVSETTASLTI 25 RPGAETSTALPTQTTSSLFTLLVTGTSRVDLSPTASPGVSAKTAPLSTHPGT ETSTMIPTSTLSLGLLETTGLLATSSSAETSTSTLTLTVSPAVSGLSSASIT TDKPQTVTSWNTETSPSVTSVGPPEFSRTVTGTTMTLIPSEMPTPPKTSHGE GVSPTTILRTTMVEATNLATTGSSPTVAKTTTTFNTLAGSLFTPLTTPGMST LASESVTSRTSYNHRSWISTTSSYNRRYWTPATSTPVTSTFSPGISTSSIPS 30 STAATVPFMVPFTLNFTITNLQYEEDMRHPGSRKFNATERELQGLLKPLFRN SSLEYLYSGCRLASLRPEKDSSATAVDAICTHRPDPEDLGLDRERLYWELSN LTNGIQELGPYTLDRNSLYVNGFTHRSSMPTTSTPGTSTVDVGTSGTPSSSP SPTTAGPLLMPFTLNFTITNLQYEEDMRRTGSRKFNTMESVLQGLLKPLFKN TSVGPLYSGCRLTLLRPEKDGAATGVDAICTHRLDPKSPGLNREQLYWELSK35LTNDIEELGPYTLDRNSLYVNGFTHQSSVSTTSTPGTSTVDLRTSGTPSSLS SPTIMAAGPLLVPFTLNFTITNLQYGEDMGHPGSRKFNTTERVLQGLLGPIF KNTSVGPLYSGCRLTSLRSEKDGAATGVDAICIHHLDPKSPGLNRERLYWEL SQLTNGIKELGPYTLDRNSLYVNGFTHRTSVPTSSTPGTSTVDLGTSGTPFS LPSPATAGPLLVLFTLNFTITNLKYEEDMHRPGSRKFNTTERVLQTLLGPMF 40 KNTSVGLLYSGCRLTLLRSEKDGAATGVDAICTHRLDPKSPGVDREQLYWEL SQLTNGIKELGPYTLDRNSLYVNGFTHWIPVPTSSTPGTSTVDLGSGTPSSL PSPTTAGPLLVPFTLNFTITNLKYEEDMHCPGSRKFNTTERVLQSLLGPMFK NTSVGPLYSGCRLTLLRSEKDGAATGVDAICTHRLDPKSPGVDREQLYWELS QLTNGIKELGPYTLDRNSLYVNGFTHQTSAPNTSTPGTSTVDLGTSGTPSSL 45 PSPTSAGPLLVPFTLNFTITNLQYEEDMHHPGSRKFNTTERVLQGLLGPMFK NTSVGLLYSGCRLTLLRPEKNGAATGMDAICSHRLDPKSPGLNREQLYWELS QLTHGIKELGPYTLDRNSLYVNGFTHRSSVAPTSTPGTSTVDLGTSGTPSSL PSPTTAVPLLVPFTLNFTITNLQYGEDMRHPGSRKFNTTERVLQGLLGPLFK NSSVGPLYSGCRLISLRSEKDGAATGVDAICTHHLNPQSPGLDREQLYWQLS50QMTNGIKELGPYTLDRNSLYVNGFTHRSSGLTTSTPWTSTVDLGTSGTPSPV PSPTTTGPLLVPFTLNFTITNLQYEENMGHPGSRKFNITESVLQGLLKPLFK STSVGPLYSGCRLTLLRPEKDGVATRVDAICTHRPDPKIPGLDRQQLYWELS QLTHSITELGPYTLDRDSLYVNGFTQRSSVPTTSTPGTFTVQPETSETPSSL PGPTATGPVLLPFTLNFTITNLQYEEDMRRPGSRKFNTTERVLQGLLMPLFK 55 NTSVSSLYSGCRLTLLRPEKDGAATRVDAVCTHRPDPKSPGLDRERLYWKLS 45 Attorney Docket No.07917-0454WO1 / UMMS 24-66 QLTHGITELGPYTLDRHSLYVNGFTHQSSMTTTRTPDTSTMHLATSRTPASL SGPMTASPLLVLFTINFTITNLRYEENMHHPGSRKFNTTERVLQGLLRPVFK NTSVGPLYSGCRLTLLRPKKDGAATKVDAICTYRPDPKSPGLDREQLYWELS QLTHSITELGPYTLDRDSLYVNGFTQRSSVPTTSIPGTPTVDLGTSGTPVSK 5 PGPSAASPLLVLFTLNFTITNLRYEENMQHPGSRKFNTTERVLQGLLRSLFK STSVGPLYSGCRLTLLRPEKDGTATGVDAICTHHPDPKSPRLDREQLYWELS QLTHNITELGPYALDNDSLFVNGFTHRSSVSTTSTPGTPTVYLGASKTPASI FGPSAASHLLILFTLNFTITNLRYEENMWPGSRKFNTTERVLQGLLRPLFKN TSVGPLYSGCRLTLLRPEKDGEATGVDAICTHRPDPTGPGLDREQLYLELSQ 10 LTHSITELGPYTLDRDSLYVNGFTHRSSVPTTSTGVVSEEPFTLNFTINNLR YMADMGQPGSLKFNITDNVMQHLLSPLFQRSSLGARYTGCRVIALRSVKNGA ETRVDLLCTYLQPLSGPGLPIKQVFHELSQQTHGITRLGPYSLDKDSLYLNG YNEPGPDEPPTTPKPATTFLPPLSEATTAMGYHLKTLTLNFTISNLQYSPDM GKGSATFNSTEGVLQHLLRPLFQKSSMGPFYLGCQLISLRPEKDGAATGVDT 15 TCTYHPDPVGPGLDIQQLYWELSQLTHGVTQLGFYVLDRDSLFINGYAPQNL SIRGEYQINFHIVNWNLSNPDPTSSEYITLLRDIQDKVTTLYKGSQLHDTFR FCLVTNLTMDSVLVTVKALFSSNLDPSLVEQVFLDKTLNASFHWLGSTYQLV DIHVTEMESSVYQPTSSSSTQHFYLNFTITNLPYSQDKAQPGTTNYQRNKRN IEDALNQLFRNSSIKSYFSDCQVSTFRSVPNRHHTGVDSLCNFSPLARRVDR 20 VAIYEEFLRMTRNGTQLQNFTLDRSSVLVDGYSPNRNEPLTGNSDLPFWAVI LIGLAGLLGVITCLICGVLVTTRRRKKEGEYNVQQQCPGYYQSHLDLEDLQ (SEQ ID NO: 20) In some embodiments, an RNA polynucleotide disclosed herein can encode a Muc16 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein 25 can encode a Muc16 polypeptide wherein the Muc16 polypeptide comprises an amino acid sequence that is at least about or about 50%, 55%, 60%, 655, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 20. In some embodiments, an RNA polynucleotide disclosed herein can encode a Muc16 polypeptide comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, an RNA30polynucleotide disclosed herein can encode a Muc16 polypeptide consisting of the amino acid sequence of SEQ ID NO: 20. An RNA polynucleotide of the present disclosure can encode prominin-1 (CD133), an isoform, and / or a variant of CD133. The amino acid sequence of CD133 (Homo sapiens) is: 35 MALVLGSLLLLGLCGNSFSGGQPSSTDAPKAWNYELPATNYETQDSHKAGPI GILFELVHIFLYVVQPRDFPEDTLRKFLQKAYESKIDYDKPETVILGLKIVY YEAGIILCCVLGLLFIILMPLVGYFFCMCRCCNKCGGEMHQRQKENGPFLRK CFAISLLVICIIISIGIFYGFVANHQVRTRIKRSRKLADSNFKDLRTLLNET PEQIKYILAQYNTTKDKAFTDLNSINSVLGGGILDRLRPNIIPVLDEIKSMA 40 TAIKETKEALENMNSTLKSLHQQSTQLSSSLTSVKTSLRSSLNDPLCLVHPS SETCNSIRLSLSQLNSNPELRQLPPVDAELDNVNNVLRTDLDGLVQQGYQSL NDIPDRVQRQTTTVVAGIKRVLNSIGSDIDNVTQRLPIQDILSAFSVYVNNT ESYIHRNLPTLEEYDSYWWLGGLVICSLLTLIVIFYYLGLLCGVCGYDRHAT PTTRGCVSNTGGVFLMVGVGLSFLFCWILMIIVVLTFVFGANVEKLICEPYT 45 SKELFRVLDTPYLLNEDWEYYLSGKLFNKSKMKLTFEQVYSDCKKNRGTYGT 46 Attorney Docket No.07917-0454WO1 / UMMS 24-66 LHLQNSFNISEHLNINEHTGSISSELESLKVNLNIFLLGAAGRKNLQDFAAC GIDRMNYDSYLAQTGKSPAGVNLLSFAYDLEAKANSLPPGNLRNSLKRDAQT IKTIHQQRVLPIEQSLSTLYQSVKILQRTGNGLLERVTRILASLDFAQNFIT NNTSSVIIEETKKYGRTIIGYFEHYLQWIEFSISEKVASCKPVATALDTAVD 5 VFLCSYIIDPLNLFWFGIGKATVFLLPALIFAVKLAKYYRRMDSEDVYDDVE TIPMKNMENGNNGYHKDHVYGIHNPVMTSPSQH (SEQ ID NO: 21) In some embodiments, an RNA polynucleotide disclosed herein can encode a CD133 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode a CD133 polypeptide wherein the CD133 polypeptide comprises an amino 10 acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 21. In some embodiments, an RNA polynucleotide disclosed herein can encode a CD133 polypeptide comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, an RNA polynucleotide disclosed herein can encode a CD133 polypeptide consisting of the amino acid15sequence of SEQ ID NO: 21. An RNA polynucleotide of the present disclosure can encode cadherin 3 (CDH3), an isoform, and / or a variant of CDH3. The amino acid sequence of CDH3 (Homo sapiens) is: MGLPRGPLASLLLLQVCWLQCAASEPCRAVFREAEVTLEAGGAEQEPGQALG20KVFMGCPGQEPALFSTDNDDFTVRNGETVQERRSLKERNPLKIFPSKRILRR HKRDWVVAPISVPENGKGPFPQRLNQLKSNKDRDTKIFYSITGPGADSPPEG VFAVEKETGWLLLNKPLDREEIAKYELFGHAVSENGASVEDPMNISIIVTDQ NDHKPKFTQDTFRGSVLEGVLPGTSVMQVTATDEDDAIYTYNGVVAYSIHSQ EPKDPHDLMFTIHRSTGTISVISSGLDREKVPEYTLTIQATDMDGDGSTTTA 25 VAVVEILDANDNAPMFDPQKYEAHVPENAVGHEVQRLTVTDLDAPNSPAWRA TYLIMGGDDGDHFTITTHPESNQGILTTRKGLDFEAKNQHTLYVEVTNEAPF VLKLPTSTATIVVHVEDVNEAPVFVPPSKVVEVQEGIPTGEPVCVYTAEDPD KENQKISYRILRDPAGWLAMDPDSGQVTAVGTLDREDEQFVRNNIYEVMVLA MDNGSPPTTGTGTLLLTLIDVNDHGPVPEPRQITICNQSPVRQVLNITDKDL 30 SPHTSPFQAQLTDDSDIYWTAEVNEEGDTVVLSLKKFLKQDTYDVHLSLSDH GNKEQLTVIRATVCDCHGHVETCPGPWKGGFILPVLGAVLALLFLLLVLLLL VRKKRKIKEPLLLPEDDTRDNVFYYGEEGGGEEDQDYDITQLHRGLEARPEV VLRNDVAPTIIPTPMYRPRPANPDEIGNFIIENLKAANTDPTAPPYDTLLVF DYEGSGSDAASLSSLTSSASDQDQDYDYLNEWGSRFKKLADMYGGGEDD35(SEQ ID NO: 22) In some embodiments, an RNA polynucleotide disclosed herein can encode a CDH3 polypeptide. In some embodiments, an RNA polynucleotide disclosed herein can encode a CDH3 polypeptide wherein the CDH3 polypeptide comprises an amino acid sequence that is at least about or about 70%, 75%, 80%, 85%, 90%, 95%, or 99% 40 identical to SEQ ID NO: 22. In some embodiments, an RNA polynucleotide disclosed herein can encode a CDH3 polypeptide comprising the amino acid sequence 47 Attorney Docket No.07917-0454WO1 / UMMS 24-66 of SEQ ID NO: 22. In some embodiments, an RNA polynucleotide disclosed herein can encode a CDH3 polypeptide consisting of the amino acid sequence of SEQ ID NO: 22. Provided herein is a composition comprising at least one RNA polynucleotide 5 as disclosed herein encoding a tumor antigen polypeptide (e.g., a monotherapy composition comprising an RNA polynucleotide encoding a tumor antigen polypeptide). In some embodiments, a composition disclosed herein can comprise more than one RNA polynucleotides encoding a tumor antigen polypeptide. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least 10 about or about two, three, or more than three RNA polynucleotides encoding a tumor antigen polypeptide as disclosed herein. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least one RNA polynucleotide encoding a tumor antigen selected from the group of tumor antigen polypeptides consisting of MSLN, Muc1, PSMA, EGFR, 15 ROR1, TF, CEA, HER2, TROP2, CLDN18.2, MUC16, CD133, and CDH3. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least one RNA polynucleotide encoding a tumor antigen selected from the group of tumor antigen polypeptides consisting of MSLN, Muc1, and PSMA. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least about or about 20 two or three RNA polynucleotides encoding a tumor antigen selected from the group of tumor antigen polypeptides consisting of MSLN, Muc1, and PSMA. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise three RNA polynucleotides that encode for the tumor antigen polypeptides MSLN, Muc1, and PSMA (e.g., an RNA polynucleotide that encodes for MSLN, an 25 RNA polynucleotide that encodes for Muc1, and an RNA polynucleotide that encodes for PSMA). In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise three RNA polynucleotides that encode for tumor antigen polypeptides wherein the ratio of RNA polynucleotide that encodes for MSLN: RNA polynucleotide that encodes for Muc1: RNA polynucleotide that encodes for PSMA is 30 1:1:1. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise about 10 μg to about 60 μg of an RNA polynucleotide that encodes for MSLN; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for Muc1; and about 10 μg to about 60 μg of an RNA polynucleotide that encodes for PSMA. In 48 Attorney Docket No.07917-0454WO1 / UMMS 24-66 some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise about 10 μg of an RNA polynucleotide that encodes for MSLN; about 10 μg of an RNA polynucleotide that encodes for Muc1; and about 10 μg of an RNA polynucleotide that encodes for PSMA wherein the total amount of RNA 5 polynucleotides in the composition is about 30 μg. Compositions (i.e., a cocktails) disclosed herein can comprise RNA polynucleotides that encode for at least one a cytokine polypeptide and at least one tumor antigen polypeptide. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least about or about 1, 2, 3, 4, 5, 6, or more than 6 10 RNA polynucleotides that encode a cytokine polypeptide, and at least about or about 1, 2, 3, or at least about or about 1, 2, 3, or more than 3 RNA polynucleotides that encode a tumor antigen polypeptide. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least one RNA polynucleotide that encodes for a cytokine polypeptide selected from the group consisting of IL-12, IL-18, IFNB1, 15 CXCL10, and CCL5, and at least one RNA polynucleotide that encodes for a tumor antigen polypeptide selected from the group consisting of MSLN, Muc1, PSMA, EGFR, ROR1, TF, CEA, HER2, TROP2, CLDN18.2, MUC16, CD133, and CDH3. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least one RNA polynucleotide that encodes for a cytokine polypeptide selected 20 from the group consisting of IL-12, IL-18, IFNB1, CXCL10, and CCL5, and at least one RNA polynucleotide that encodes for a tumor antigen polypeptide selected from the group consisting of MSLN, Muc1, and PSMA. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least about or about 1, 2, 3, 4, 5, 6, or more than 6 RNA polynucleotides that encode a cytokine polypeptide 25 selected from the group consisting of IL-12, IL-18, IFNB1, CXCL10, and CCL5 and at least about or about 1, 2, 3, or more than 3 RNA polynucleotides that encode a tumor antigen polypeptide selected from the group consisting of MSLN, Muc1, and PSMA. In some embodiments, a composition (i.e., a cocktail) disclosed herein can 30 comprise at least one RNA polynucleotide that encodes for the cytokine polypeptide IL-12; at least one RNA polynucleotide that encodes a cytokine polypeptide selected from the group consisting of IL-18, IFNB1, CXCL10, and CCL5; and at least one RNA polynucleotide that encodes a tumor antigen polypeptide selected from the 49 Attorney Docket No.07917-0454WO1 / UMMS 24-66 group consisting of MSLN, Muc1, PSMA, EGFR, ROR1, TF, CEA, HER2, TROP2, CLDN18.2, MUC16, CD133, and CDH3. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least one RNA polynucleotide that encodes for the cytokine polypeptide IL-12; at least one RNA polynucleotide that 5 encodes a cytokine polypeptide selected from the group consisting of IL-18, IFNB1, CXCL10, and CCL5; and at least one RNA polynucleotide that encodes a tumor antigen polypeptide selected from the group consisting of MSLN, Muc1, and PSMA. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise at least one RNA polynucleotide that encodes for the cytokine polypeptide IL-12; at 10 least one RNA polynucleotide that encodes a cytokine polypeptide selected from the group consisting of IL-15, IL-18, IFNB1, CXCL10, and CCL5; and at least one RNA polynucleotide that encodes a tumor antigen polypeptide selected from the group consisting of MSLN, Muc1, and PSMA. In some embodiments, a composition (i.e., a cocktail) disclosed herein can15 comprise about 5 RNA polynucleotides that encode for the cytokine polypeptides IL- 12, IL-18, IFNB1, CXCL10, and CCL5 and at least one RNA polynucleotide that encodes a tumor antigen polypeptide selected from the group consisting of MSLN, Muc1, PSMA, EGFR, ROR1, TF, CEA, HER2, TROP2, CLDN18.2, MUC16, CD133, and CDH3. In some embodiments, a composition (i.e., a cocktail) disclosed 20 herein can comprise about 5 RNA polynucleotides that encode for the cytokine polypeptides IL-12, IL-18, IFNB1, CXCL10, and CCL5 and about 3 RNA polynucleotides that encode for the tumor antigen polypeptides MSLN, Muc1, and PSMA. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise (i) five RNA polynucleotides that encode for the cytokine polypeptides 25 wherein the ratio of RNA polynucleotide that encodes for IL-12: RNA polynucleotide that encodes for IL-18: RNA polynucleotide that encodes for IFNB1: RNA polynucleotide that encodes for CXCL10: RNA polynucleotide that encodes for CCL5 is 1:1:1:1:1:1; and (ii) three RNA polynucleotides that encode for tumor antigen polypeptides wherein the ratio of RNA polynucleotide that encodes for 30 MSLN: RNA polynucleotide that encodes for Muc1: RNA polynucleotide that encodes for PSMA is 1:1:1. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise (i) about 10 μg to about 60 μg of an RNA polynucleotide that encodes for IL-12; about 10 μg to about 60 μg of an RNA 50 Attorney Docket No.07917-0454WO1 / UMMS 24-66 polynucleotide that encodes for IL-18; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for IFNB1; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for CXCL10; and about 10 μg to about 60 μg of an RNA polynucleotide that encodes for CCL5; and (ii) about 10 μg to about 60 μg of an RNA 5 polynucleotide that encodes for MSLN; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for Muc1; and about 10 μg to about 60 μg of an RNA polynucleotide that encodes for PSMA. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise (i) about 10 μg of an RNA polynucleotide that encodes for IL-12; about 10 μg of an RNA polynucleotide that encodes for IL-18; 10 about 10 μg of an RNA polynucleotide that encodes for IFNB1; about 10 μg of of an RNA polynucleotide that encodes for CXCL10; and about 10 μg of an RNA polynucleotide that encodes for CCL5; and (ii) about 10 μg of an RNA polynucleotide that encodes for MSLN; about 10 μg of an RNA polynucleotide that encodes for Muc1; and about 10 μg of an RNA polynucleotide that encodes for PSMA wherein 15 the total amount of RNA polynucleotides in the composition is about 80 μg. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise about 6 RNA polynucleotides that encode for the cytokine polypeptides IL- 12, IL-15, IL-18, IFNB1, CXCL10, and CCL5 and at least one RNA polynucleotide that encodes a tumor antigen polypeptide selected from the group consisting of 20 MSLN, Muc1, PSMA, EGFR, ROR1, TF, CEA, HER2, TROP2, CLDN18.2, MUC16, CD133, and CDH3. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise about 6 RNA polynucleotides that encode for the cytokine polypeptides IL-12, IL-15, IL-18, IFNB1, CXCL10, and CCL5 and about 3 RNA polynucleotides that encode for the tumor antigen polypeptides MSLN, Muc1, 25 and PSMA. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise (i) six RNA polynucleotides that encode for the cytokine polypeptides wherein the ratio of RNA polynucleotide that encodes for IL-12: RNA polynucleotide that encodes for IL-15: RNA polynucleotide that encodes for IL-18: RNA polynucleotide that encodes for IFNB1: RNA polynucleotide that encodes for 30 CXCL10: RNA polynucleotide that encodes for CCL5 is 1:1:1:1:1:1; and (ii) three RNA polynucleotides that encode for tumor antigen polypeptides wherein the ratio of RNA polynucleotide that encodes for MSLN: RNA polynucleotide that encodes for Muc1: RNA polynucleotide that encodes for PSMA is 1:1:1. In some embodiments, a 51 Attorney Docket No.07917-0454WO1 / UMMS 24-66 composition (i.e., a cocktail) disclosed herein can comprise (i) about 10 μg to about 60 μg of an RNA polynucleotide that encodes for IL-12; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for IL-15; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for IL-18; about 10 μg to about 60 μg of an RNA 5 polynucleotide that encodes for IFNB1; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for CXCL10; and about 10 μg to about 60 μg of an RNA polynucleotide that encodes for CCL5; and (ii) about 10 μg to about 60 μg of an RNA polynucleotide that encodes for MSLN; about 10 μg to about 60 μg of an RNA polynucleotide that encodes for Muc1; and about 10 μg to about 60 μg of an RNA 10 polynucleotide that encodes for PSMA. In some embodiments, a composition (i.e., a cocktail) disclosed herein can comprise (i) about 10 μg of an RNA polynucleotide that encodes for IL-12; about 10 μg of an RNA polynucleotide that encodes for IL-15; about 10 μg of an RNA polynucleotide that encodes for IL-18; about 10 μg of an RNA polynucleotide that encodes for IFNB1; about 10 μg of of an RNA 15 polynucleotide that encodes for CXCL10; and about 10 μg of an RNA polynucleotide that encodes for CCL5; and (ii) about 10 μg of an RNA polynucleotide that encodes for MSLN; about 10 μg of an RNA polynucleotide that encodes for Muc1; and about 10 μg of an RNA polynucleotide that encodes for PSMA wherein the total amount of RNA polynucleotides in the composition is about 90 μg. 20 Lipid Nanoparticle-Encapsulated mRNA Provided herein are lipid nanoparticles (LNPs) that encapsulate at least one RNA polynucleotide (e.g., mRNA polynucleotide) disclosed herein. Methods of preparing LNPs that can be used in the present methods and compositions herein are known in the art (see, e.g., WO / 20221 / 82767 and WO / 2024 / 238486) and can be used 25 herein with some modification. Preferably, the LNPs used herein comprise an ionizable lipid (e.g., D-Lin- MC3-DMA (MC3), SM-102, or LP01); 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); cholesterol; and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol- 2000 (DMG-PEG). Preferably, the LNPs disclosed herein can comprise about 45 30 mol% to about 55 mol% MC3; about 5 mol% to about 15 mol% DSPC; about 30 mol% to about 45 mol% cholesterol; and about 1 mol% to about 10 mol% DMG- PEG. In some embodiments, the LNPs disclosed herein can comprise (i) at least about or about 45,46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 mol% MC3; (ii) at least 52 Attorney Docket No.07917-0454WO1 / UMMS 24-66 about or about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mol% DSPC; (iii) at least about or about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 mol% cholesterol; and (iv) at least about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mol% DMG- PEG. In some embodiments, the LNPs disclosed herein can comprise about 48 mol% 5 MC3, about 10 mol% DSPC, about 37 mol% cholesterol, and about 5 mol% DMG- PEG. In some embodiments, LNPs provided herein can range in size from about 50 nm to about 70 nm in diameter. Particle size can be determined according to methods known in the art, such as dynamic light scattering (DLS). 10 In some embodiments, LNPs provided herein can have a neutral surface (i.e., zeta potential). In some embodiments, LNPs provided herein can have a zeta potential that ranges from about -10 and +10 mV. In some embodiments, charge of the LNPs disclosed herein can be measured by electrophoretic light scattering. In some embodiments, LNPs provided herein can encapsulate at least one 15 RNA polynucleotide (e.g., mRNA polynucleotide) disclosed herein with about 80% to about 100% efficiency. In some embodiments, LNPs provided herein can encapsulate about 20 μg to about 100 μg amount of RNA polynucleotides in total. Methods of measuring RNA (mRNA) encapsulation efficiency and mRNA concentration are known in the art and are suitable for use herein (see, e.g., Schober et al., Sci Rep. 2024 20 Jan 29;14(1):2403). In some embodiments, LNPs provided herein can encapsulate at least one, two, or more RNA polynucleotides (e.g., mRNA polynucleotides) that encode a cytokine polypeptide. In some embodiments, LNPs provided herein can encapsulate at least one, two, or more RNA polynucleotides (e.g., mRNA polynucleotides) that 25 encode a tumor antigen polypeptide. In some embodiments, LNPs provided herein can encapsulate at least one RNA polynucleotide that encodes a cytokine polypeptide and at least one RNA polynucleotide that encodes a tumor antigen polypeptide. Pharmaceutical Compositions and Methods of Administration The methods described herein include the use of pharmaceutical compositions 30 comprising or consisting of at least one of the RNA polynucleotides (e.g., mRNA polynucleotides) disclosed herein, compositions comprising a cocktail of RNA polynucleotides, and / or LNPs encapsulating least one of the RNA polynucleotides (e.g., mRNA polynucleotides). 53 Attorney Docket No.07917-0454WO1 / UMMS 24-66 Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. As used herein the language “pharmaceutically acceptable carrier” includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical 5 administration. Supplementary active compounds (e.g., an anti-cancer compound) can also be incorporated into the compositions. A listing of active compounds and specific drugs suitable for use herein as supplementary active compounds can be found in The Merck Index Online; Royal Society of Chemistry, 2025; rsc.org / merck- index (accessed March 12, 2025), and the United States Pharmacopeia-47 / National 10 Formulary-47, published by the United States Pharmacopeial Convention, Inc., Rockville Md., 2024. In some embodiments, a supplementary active compound can be one known in the art to treat and / or alleviate a symptom associated with a cancer (e.g., a cancer comprising a cold tumor, e.g., a pancreatic cancer). Pharmaceutical compositions are typically formulated to be compatible with 15 its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous (i.v.), intratumoral (i.t.), intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. In certain embodiments, a pharmaceutical composition of the present disclosure is formulated for systemic / intravenous (i.v.) delivery. In certain embodiments, a 20 pharmaceutical composition of the present disclosure is formulated for localized / intratumoral (i.t.) delivery. Methods of formulating suitable pharmaceutical compositions are known in the art, see, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of 25 Textbooks and Monographs (Dekker, NY). For example, solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants 30 such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The 54 Attorney Docket No.07917-0454WO1 / UMMS 24-66 parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the 5 extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of 10 manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating 15 such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it can be preferable to include isotonic agents, for example, sugars, polyalcohols such as 20 mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients 25 enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and 30 freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Pharmaceutical compositions disclosed herein can be formulated for controlled release of the active agent of interest (e.g., an RNA polynucleotide that 55 Attorney Docket No.07917-0454WO1 / UMMS 24-66 encodes a cytokine polypeptide and / or an RNA polynucleotide that encodes a tumor antigen polypeptide). For example, controlled release of the active agent of interest can be achieved through encapsulation of said active agent. In some embodiments, the active agent of interest disclosed herein can be encapsulated in liposomes, 5 microspheres, nanoparticles, and the like. See, e.g., U.S. Patent No. 5,413,797; Timko et al., Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1349-54; Merkus, Henk G., Gabriel MH Meesters, and Wim Oostra, eds. PARTICLES AND NANOPARTICLES IN PHARMACEUTICAL PRODUCTS: DESIGN, MANUFACTURING, BEHAVIOR AND PERFORMANCEVol. 29. Springer, 2018; and Tadros, Tharwat F. BASIC PRINCIPLES OF10 FORMULATION TYPES Vol. 2. Walter de Gruyter GmbH & Co KG, 2018. In some embodiments, pharmaceutical compositions comprising an encapsulated active agent of interest can be formulated for and administered by intravenous (i.v.) delivery and / or intratumoral (i.t.) delivery. The present disclosure also provides cancer vaccine formulations. Cancer 15 vaccines contemplated herein are formulated to comprise an effective amount of an RNA polynucleotide that encodes a cytokine polypeptide and / or an RNA polynucleotide that encodes a tumor antigen to produce an antigen-specific immune response in a subject. In some embodiments, a cancer vaccine disclosed herein can be administered to a subject who is genetically predisposed to a cancer that comprises a 20 cold tumor (e.g., a pancreatic cancer). Methods of screening a tumor for genetic markers is known in the art and suitable for use herein (Quraish et al., Cancer Inform. 2023 Feb 1;22:11769351221150772). In some embodiments, a cancer vaccine disclosed herein can be administered to a subject before, during, or after administration of an anti-cancer therapy such as, but not limited to other traditional 25 cancer vaccines, chemotherapies, radiation therapies, surgery, hormonal therapies, and / or biological therapies / immunotherapies. In some embodiments, cancer vaccines of the present disclosure can include a pharmaceutically acceptable carrier such as those disclosed herein. In some embodiments, cancer vaccines contemplated herein can be formulated and / or30 administered without an adjuvant. In some embodiments, an adjuvant is not co- formulated with the cancer vaccines contemplated herein. Optionally, in some embodiments, an adjuvant is co-formulated and / or co-administered with the cancer vaccines contemplated herein. Non-limiting examples of adjuvants suitable for use in 56 Attorney Docket No.07917-0454WO1 / UMMS 24-66 the cancer vaccines disclosed herein are known in art (see, e.g., Xie et al., NPJ Vaccines. 2023 Oct 26;8(1):162; Gote et al., Int J Mol Sci.2023 Jan 31;24(3):2700; Marriott et al. Cancer Treat Res Commun. 2023;34:100667). In some embodiments, an adjuvant suitable for use herein can include incomplete Freund's adjuvant (IFA 5 (e.g., Montanide ISA-51)), polyinosinic:polycytidylic acid (poly I:C), granulocyte- macrophage colony-stimulating factor (GM-CSF (e.g., sargramostim)), interleukin-2 (IL-2 (e.g., aldesleukin)), or any combination thereof. The pharmaceutical compositions and / or cancer vaccines disclosed herein can be included in a container, pack, or dispenser together with instructions for 10 administration. A kit comprising the plasmids encoding an active agent of interest (e.g., an RNA polynucleotide that encodes a cytokine polypeptide and / or an RNA polynucleotide that encodes a tumor antigen polypeptide) and instructions for preparing a purified RNA polynucleotide for use in the methods disclosed herein is also contemplated in the present disclosure. Such kits can further include at least one 15 material for use in preparing the purified RNA polynucleotide (e.g., reagents for an IVT reaction, a cellulose purification column). In some embodiments, a kit of the present disclosure can also include an active agent of interest (e.g., an RNA polynucleotide that encodes a cytokine polypeptide and / or an RNA polynucleotide that encodes a tumor antigen polypeptide) and instructions for encapsulating the 20 active agent in a LNP suitable for use in the methods disclosed herein. These kits can further include at least one material for use in preparing the LNP-encapsulated RNA. Methods of Treatment The compositions described herein can be used to treat subjects with cancer, e.g., a cancer that comprises a cold tumor. Examples of cancers that can be treated 25 with the compositions described herein can include ovarian cancer, breast cancer, brain cancer, prostate cancer, pancreatic cancer, or any metastasis thereof. In some embodiments, cancers that can be treated with the compositions described herein include pancreatic cancers. Pancreatic cancers (e.g., pancreatic ductal adenocarcinoma (PDAC)) are considered to comprise “cold” tumors because the 30 tumor immune microenvironment exhibits poor intratumoral T-cell infiltration. In some embodiments, the pancreatic cancer to be treated according to the methods disclosed herein comprises pancreatic ductal adenocarcinoma (PDAC), squamous cell 57 Attorney Docket No.07917-0454WO1 / UMMS 24-66 carcinoma, adenosquamous carcinoma, colloid carcinoma, pancreatic neuroendocrine tumors (NETs), or any combination thereof. As used herein, the terms "patient" and "subject" and similar phrases can be used interchangeably and are intended to refer to subjects who are at risk for and / or 5 have been diagnosed with a cancer (e.g., a cancer that comprises a cold tumor, e.g., a pancreatic cancer). In certain embodiments, the compositions described herein can be used to treat a subject who is at risk for and / or have been diagnosed with a cancer that comprises a cold tumor (e.g., a pancreatic cancer). Preferable, the subject is human, but the methods can be used in other mammals, e.g., non-human veterinary subjects 10 such as non-human primates, cats, dogs, horses, cows, goats, and rabbits. Methods of determining whether a cancer comprises a cold tumor are known in the art and can include genetic sequencing of tumor cells or tissue or liquid biopsies, e.g., to detect genetic markers (see, e.g., Quraish et al., Cancer Inform. 2023 Feb 1;22:11769351221150772). In some embodiments, a subject can have or can be 15 suspected of having cancer, a tumor (e.g., a cold tumor), or any combination thereof. In some embodiments, a subject can have or can be suspected of having one or more primary tumors, one or more metastatic tumors such as solid tumors or any combination thereof. In some embodiments, a subject can be a human patient. In some embodiments, a human patient such as an adult, child, adolescent, toddler, 20 young adult or infant or fetus who is in need of the methods herein can be identified by routine medical examination, e.g., laboratory tests, biopsy, magnetic resonance imaging (MRI) scans, ultrasound exams, and the like. The methods disced herein generally include administering a therapeutically effective amount of a composition disclosed herein (e.g., compositions comprising or 25 consisting of at least one of the RNA polynucleotides (e.g., mRNA polynucleotides) that encodes a cytokine polypeptide and / or a tumor antigen polypeptide; compositions comprising a cocktail of RNA polynucleotides as disclosed herein, and / or LNPs encapsulating least one of the RNA polynucleotides disclosed herein). In some embodiments, methods disclosed herein can include administering a therapeutically 30 effective amount of a composition disclosed herein, wherein a therapeutically effective amount of the composition treats, prevents, or attenuates a cancer (e.g., a cancer that comprises a cold tumor, e.g., gliomas, breast, ovarian, prostate, and / or pancreatic cancers) or a symptom thereof. Symptoms of these cancers and methods of 58 Attorney Docket No.07917-0454WO1 / UMMS 24-66 measuring said symptoms, symptom progression, as well as progression of the cancer (e.g., staging, tumor growth, ect.) are generally known in the art and are suitable for use herein (see, e.g., Debinski W, editor. Gliomas [Internet]. Brisbane (AU): Exon Publications; 2021 Apr 30 (ncbi.nlm.nih.gov / books / NBK570706 – accessed on May 5 21, 2025); and StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan (ncbi.nlm.nih.gov / books / NBK430685 / – accessed on May 21, 2025). In some embodiments, methods disclosed herein can include administering a therapeutically effective amount of a composition disclosed herein, wherein a therapeutically effective amount of the composition can reduce expansion of, shrink 10 the tumor, kill tumor cells, prevent the occurrence of metastases from the primary tumor, reduce the number of tumor cells of a tumor, primary tumor and / or a metastatic tumor, inhibit the growth of tumor cells of a primary tumor and / or a metastatic tumor, eliminate tumor cells in a subject by killing the cells or preventing propagation or expansion of the solid tumor cells and the like. 15 In some embodiments, methods disclosed herein can include administering a therapeutically effective amount of a composition disclosed herein, wherein the composition comprises at least one of the RNA polynucleotides (e.g., mRNA polynucleotides) that encodes a cytokine polypeptide. In some embodiments, methods disclosed herein can include administering a therapeutically effective amount 20 of a composition disclosed herein, wherein the composition comprises at least one of the RNA polynucleotides (e.g., mRNA polynucleotides) that encodes a tumor antigen polypeptide. In some embodiments, methods disclosed herein can include administering a therapeutically effective amount of a composition disclosed herein, wherein the composition comprises at least one of the RNA polynucleotides that 25 encodes a cytokine polypeptide and at least one of the RNA polynucleotides that encodes a tumor antigen polypeptide. In some embodiments, methods disclosed herein can include administering (i) a therapeutically effective amount of a composition that comprises at least one of the RNA polynucleotides that encodes a cytokine polypeptide and (ii) a therapeutically 30 effective amount of a composition that comprises at least one of the RNA polynucleotides that encodes a tumor antigen polypeptide. In some embodiments, the composition comprising at least one RNA polynucleotide encoding a cytokine polypeptide can be administered before, simultaneously, and / or after administration of 59 Attorney Docket No.07917-0454WO1 / UMMS 24-66 the composition comprising at least one RNA polynucleotide encoding a tumor antigen polypeptide. As used herein the terms “administer,” “administering,” and “administration” are intended to mean introducing at least one an active agent of interest (e.g., an RNA 5 polynucleotide that encodes a cytokine polypeptide and / or an RNA polynucleotide that encodes a tumor antigen polypeptide) into a subject. When administration is for the purpose of treatment, the agent can be provided before, during, and / or after the onset of or progression of a symptom or sign of the cancer (e.g., a cancer that comprises a cold tumor, e.g., gliomas, breast, ovarian, prostate, and / or pancreatic 10 cancers). In some embodiments, the methods can include systemic administration (e.g., by i.v.) of one or more doses of the agent to treat the cancer in the subject. In some embodiments, the methods can include local administration to the tumor (e.g., by i.t.) of one or more doses of the agent to treat the cancer in the subject. Administration of a therapeutically effective amount of a treatment described herein 15 can result in a reduction in tumor size or decreased growth rate, a reduction in risk or frequency of reoccurrence, a delay in reoccurrence, a reduction in metastasis, increased survival, and / or decreased morbidity and mortality, inter alia. The methods of the present disclosure can also include administration of at least one tumor therapeutic agent in combination with compositions described herein. 20 For example, the methods of the present disclosure can include administration of at least one anti-cancer therapy in combination with a composition described herein. Non-limiting examples of anti-cancer therapy can include traditional cancer vaccines, chemotherapies, radiation therapies, surgery, hormonal therapies, and / or biological therapies / immunotherapies. An anti-cancer therapy for use herein can be a compound 25 with antitumor activity. Examples of compounds with antitumor activity can include (i) tubulin inhibitors, such as maytanin derivatives (DM1, DM4), monomethyl orrestatin E (MMAE), monomethyl orrestatin F (MMAF); (ii) toxins that act on DNA, such as duocarmycin, pyrrolobenzodiazepine (PBD); and / or (iii) topoisomerase inhibitors, camptothecin, SN38, Exatecan, Dxd. An anti-cancer therapy for use herein 30 can be a cytotoxic drug. A "cytotoxic drug" as used herein refers to a substance that directly or indirectly inhibits or prevents the function of cells and / or causes destruction of the cells (e.g., cancer cells). A cytotoxic drug can include e.g., chemotherapeutic agents, enzymes, antibiotics, toxins such as small molecule toxins 60 Attorney Docket No.07917-0454WO1 / UMMS 24-66 or enzymatically active toxins, toxoids, vincas, taxanes, maytansinoids or maytansinoid analogs, tomaymycin or pyrrolobenzodiazepine derivatives, cryptophycin derivatives, leptomycin derivatives, auristatin or dolastatin analogs, prodrugs, topoisomerase I inhibitors, topoisomerase II inhibitors, DNA alkylating 5 agents, anti-tubulin agents, CC-1065 and CC-1065 analogs. In some embodiments, a chemotherapeutic agent suitable for use herein can comprise an imidazotetrazine chemotherapeutic agent (e.g., temozolomide (TMZ), dacarbazine). In some embodiments, a chemotherapeutic agent suitable for use herein can comprise a platinum-containing chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin). 10 An anti-cancer therapy for use herein can comprise one or more immune checkpoint inhibitors. In some embodiments. the immune checkpoint inhibitor can be a PD-1, PD-L1, PD-L2, and / or CTLA-4 inhibitor. In some embodiments, the immune checkpoint inhibitor can be nivolumab, pembrolizumab, tremelimumab, ipilimumab, cemiplimab, MPDL3280A, AMP-224, AMP-514 and PDR001, atezolizumab, 15 Avelumab, Durvalumab, BMS-936559, CK-301, tislelizumab, toripalimab, envafolimab, HLX10, HLX20, or any combination thereof. In some embodiments, administration of a composition disclosed herein can impair tumor growth compared to tumor growth in an untreated subject with identical disease condition and predicted outcome. In some embodiments, tumors treated in the 20 subject using a composition of the present disclosure can result in the shrinking of a tumor in comparison to the starting size of the tumor in a subject. In some embodiments, a tumor treated with compositions disclosed herein can shrink by at least about or about 5% or more (e.g., about 5%, 10%, 15%, 20%, 25%, 30%, 35% 40%, 45% or 50% more) or shrink by 100% (where the tumor is eradicated and no 25 tumor cells remain from the treated tumor) compared to the measured starting size of the tumor taken before administering a composition according to the methods disclosed herein. In some embodiments, tumors of a subject can be assessed (e.g., measured) in response to a treatment regimen disclosed herein in order to modify the treatment regimen or maintain the current regimen depending on outcome at the time 30 of evaluation. In some embodiments, administration of a composition disclosed herein can improve life expectancy of a subject compared to the life expectancy of an untreated subject with identical disease condition and predicted outcome. As used herein, “life 61 Attorney Docket No.07917-0454WO1 / UMMS 24-66 expectancy of a subject” can refer to the time at which 50 percent of subjects are alive and 50 percent have passed away. In some embodiments, life expectancy can be indefinite following treatment with a composition disclosed herein. In some embodiments, life expectancy can be increased at least about or about 5% or more 5 (e.g., about 5%, 10%, 15%, 20%, 25%, 30%, 35% 40%, 45% or 50% more) compared to the life expectancy of an untreated subject with identical disease condition and predicted outcome. In some embodiments, administration of a composition disclosed herein can depend on the cancer type, grade of cancer, stage or cancer or a combination thereof. 10 In some embodiments, administration of a composition disclosed herein can depend on depend on the stage of cancer as determined by the TNM system wherein “T” stands for tumor, “N” stands for node, and “M” stands for metastasis. When applying the TNM system, the following are considered: Tumor (T)—How large is the primary tumor? Where is it located?; Node (N)—Has the tumor spread to the lymph nodes? If 15 so, where and how many nodes are involved?; and Metastasis (M)—Has the cancer spread to other parts of the body, affected other organs? If so, where and how severe? See, e.g., Rosen & Sapra, TNM Classification. [Updated 2023 Feb 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan. Available from ncbi.nlm.nih.gov / books / NBK553187 – accessed May 28, 2025. 20 In some embodiments, compositions and methods disclosed herein can be used to treat a Stage I, Stage II, Stage III, or Stage IV cancer (e.g., PDAC) in a subject. In some embodiments, administration of a composition disclosed herein can improve a Stage IV cancer in a subject to a Stage I, Stage II, or Stage III cancer. In some embodiments, administration of a composition disclosed herein can improve a 25 Stage III cancer in a subject to a Stage I or Stage II cancer. In some embodiments, administration of a composition disclosed herein can improve a Stage II cancer in a subject to a Stage I cancer. EXAMPLES The invention is further described in the following examples, which do not 30 limit the scope of the invention described in the claims. Materials and Methods The following materials and methods were used in the Examples below. 62 Attorney Docket No.07917-0454WO1 / UMMS 24-66 mRNA synthesis and purification Plasmids encoding the gene of interest were cloned into the pUC19 backbone with T7 promoter and linearized downstream of the poly(A) signal using EcoRI restriction digestion (New England Biolabs). mRNA synthesis was performed using 5 T7 RNA polymerase (CellScript) in the presence of a modified nucleotide mix, wherein uridine 5′-triphosphate (UTP) was substituted with N1-methylpseudouridine- 5′-triphosphate (m¹ΨTP) (Trilink) to enhance RNA stability and reduce immunogenicity. The in vitro transcription (IVT) reaction also included ATP, CTP, and GTP at equimolar concentrations. Following transcription, the RNA was capped 10 using a 7-methylguanosine (m⁷G) cap analog (CellScript) to ensure efficient translation. A poly(A) tail was encoded in the DNA template to produce a polyadenylated transcript. The resulting capped and polyadenylated mRNA was purified using cellulose column chromatography to remove double-stranded RNA contaminants (Messenger Bio). 15 Cytokine array KPC1 cells were plated in six-well plates and treated with cytokine-encoding mRNA cocktail for 24 hours (h). Conditioned media was then collected, and cells were trypsinized and counted using a Countess II cell counter (Invitrogen). Media samples were normalized to cell number by dilution with fresh culture media. A 75^μl 20 aliquot of each sample was analyzed using the Mouse Cytokine / Chemokine 44-Plex multiplex immunoassay (Eve Technologies). For in vivo studies, KPC1 orthotopic transplant mice or genetically engineered mouse models (GEMMs) were treated with cytokine-encoding mRNAs, either via intratumoral injection or systemic delivery using lipid nanoparticles (LNPs). Tumors, 25 livers, and blood samples were collected at designated time points. Tumor tissues were mechanically dissociated using the MACS Dissociator (Miltenyi Biotec) prior to protein extraction. Total protein concentrations were quantified using the Bradford assay. A total of 100^μl of each normalized sample was analyzed using the Mouse Cytokine / Chemokine 44-Plex multiplex immunoassay (Eve Technologies). 30 Flow analysis To assess surface MHC-I expression on KPC cells cultured in vitro, mRNA- treated cells were harvested by trypsinization, resuspended in PBS containing 2% FBS, and stained with anti-H-2K^b antibody (1:200; AF6-88.5.5.3, eBioscience, 63 Attorney Docket No.07917-0454WO1 / UMMS 24-66 RRID: AB_2937354) for 30 minutes on ice. Flow cytometry was performed on a BD LSR II cytometer, and data were analyzed using FlowJo software (TreeStar). For in vivo analysis, pancreatic tumors were isolated from treated tumor- bearing type mice. Pancreatic tumors were minced and enzymatically dissociated 5 using the gentleMACS Octo Dissociator with heaters (Miltenyi Biotec) in collagenase buffer (1× HBSS with calcium and magnesium, 1^mg / ml collagenase V, and 0.1^mg / ml DNase I) using the 37C_m_TDK1_1 program. Other tissues were chopped into ~1^mm fragments and digested in 1^mg / ml collagenase V in serum-free DMEM at 37°C for 1 hour. Following digestion, tissues were passed through 70-μm strainers, 10 centrifuged, and resuspended in PBS + 2% FBS. Red blood cells were lysed using ACK lysis buffer (Quality Biological). Single-cell suspensions were stained on ice for 30 minutes with the following antibodies (dilutions in parentheses): CD45 BV605 (1:400), CD11b BUV395 (1:1280), CD69 BV711 (1:100), CD44 (1:200), CD62L PE (1:200), NK1.1 PE-Cy7 15 (1:200), B220 PerCP-Cy5.5 (1:100), CD3 BV650 (1:300), CD8 PerCP-Cy5.5 (1:300), CD4 APC-Cy7 (1:100), CD11c BV785 (1:100), F4 / 80 APC (1:200), MHC-II PE (1:200), GR-1 PE-Dazzle 594 (1:200), PD-1 PE-Cy5 (1:200), LAG-3 BV785 (1:200), and CTLA-4 BV650 (1:200). DAPI was used to exclude dead cells, and the lipophilic carbocyanines DiI / DiD (DiIC18(3) / DiIC18(5)) were included for nanoparticle tracking. 20 Flow cytometry was performed using BD LSR II or FACSymphony A5 instruments, and data were analyzed using FlowJo software. For intracellular cytokine staining, tumor-derived single-cell suspensions were incubated in RPMI-1640 supplemented with 10% FBS and penicillin / streptomycin, and stimulated with PMA (20^ng / ml), ionomycin (1^μg / ml), and monensin (2^μM) for 25 4 hours at 37°C. Surface staining was performed with CD45 BV605 (1:400), NK1.1 PE-Cy7 (1:200), CD3 BV650 (1:300), CD8 PE-Cy7 (1:400), and CD4 PE-Cy5 (1:200), followed by fixation and permeabilization using the Foxp3 / transcription factor staining buffer set (eBioscience). Intracellular cytokine staining was conducted using GZMB APC (1:100), IFN-γ V450 (1:100), and TNF-α PE-Cy7 (1:100). 30 Cytokine expression was analyzed in CD3⁻NK1.1⁺ NK cells and CD3⁺CD4⁺ or CD8⁺ T cells. 64 Attorney Docket No.07917-0454WO1 / UMMS 24-66 Immunohistochemistry Tissues were fixed overnight in 10% neutral-buffered formalin, embedded in paraffin, and sectioned at 5^μm thickness. Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were performed using standard protocols. For 5 IHC, paraffin-embedded sections were deparaffinized, rehydrated through a graded ethanol series, and subjected to antigen retrieval by boiling in 10^mM citrate buffer (pH 6.0) for 15 minutes in a pressure cooker. Endogenous peroxidase activity was quenched with 3% hydrogen peroxide for 20 minutes, followed by two PBS washes. Sections were then incubated overnight at 4°C with the following primary antibodies: 10 CD3 (1:200), CD8 (1:100), NK1.1 (1:100), Ki67 (1:100), GZMB (1:100), and Cleaved Caspase-3 (CC3, 1:200), SMA (1:500). The next day, HRP-conjugated secondary antibodies (Vectastain Elite ABC-HRP Kits: Rat and Rabbit) were applied for 30 minutes and visualized using 3,3′-diaminobenzidine (DAB; Vector Laboratories). Images were acquired using an Olympus BX41TF microscope. CD3⁺, 15 CD8⁺, NK1.1⁺, Ki67⁺, GZMB⁺, and CC3⁺, SMA+cells were quantified by averaging counts from 5–10 high-power fields (20 × magnification) per section using ImageJ software. Tumor necrosis was assessed by calculating the percentage of total PDAC tumor area occupied by necrotic tissue in H&E-stained sections using ImageJ. Imaging and analysis were not conducted in a blinded fashion. 20 Pancreatic orthotopic transplant models Orthotopic pancreatic tumors were established by transplanting KPC1 or KPC 2838c3 cells into the pancreases of 8- to 12-week-old female C57BL / 6 mice. KPC1 cells (4 × 10⁴) or KPC 2838c3 cells (1 × 10⁵) were resuspended in 25^μl of Matrigel (BD), diluted 1:1 with cold advanced DMEM / F12 medium. Mice were anesthetized 25 using 2–3% isoflurane, and a small incision was made on the left flank to expose the pancreas. The cell suspension was injected into the tail region of the pancreas using a Hamilton syringe, and successful delivery was confirmed by the formation of a fluid bleb without leakage into the abdominal cavity. The abdominal wall was closed with absorbable Vicryl sutures (Ethicon), and the skin was secured with wound clips 30 (CellPoint Scientific Inc). Tumor growth was monitored by ultrasound imaging. Ten to twelve days after implantation, mice were randomized into treatment groups based on tumor volume. Upon euthanasia, each pancreatic tumor was divided for downstream analyses: a portion was fixed in 10% formalin for H&E and IHC 65 Attorney Docket No.07917-0454WO1 / UMMS 24-66 staining; another was embedded in optimal cutting temperature (OCT) compound and frozen for immunofluorescence; and the remaining tissue was digested into a single- cell suspension for flow cytometry. KPC GEMM 5 KPC genetically engineered mouse models (GEMMs) were generated by interbreeding P48-Cre, Kras^LSL-G12D / wt, and Trp53^fl / wt strains (C57BL / 6 background; RRIDs: P48-Cre, IMSR_JAX:023329; Kras^LSL-G12D / wt, IMSR_JAX:008179; Trp53^fl / fl, IMSR_JAX:008462). Male and female KPC mice aged 3 to 8 months were used for all experiments. Tumor progression was monitored 10 by ultrasound imaging, and mice were enrolled and randomized into treatment groups once tumors reached approximately 30^mm³ in volume for immunohistochemistry or survival analysis. Intratumoral mRNA delivery For intratumoral mRNA delivery, orthotopic pancreatic tumors were 15 established as described herein. At 10–12 days post-implantation, tumor presence and volume were confirmed using ultrasound imaging. Mice were lightly anesthetized with isoflurane to minimize movement during injection. One investigator gently palpated the abdomen to locate and stabilize the tumor near the surface, while a second investigator administered the mRNA formulation directly into the tumor using 20 a Hamilton syringe. Care was taken to avoid leakage and ensure accurate delivery into the tumor mass. Mice were monitored post-injection and tumor progression was tracked using serial ultrasound imaging. Ultrasound imaging High-resolution ultrasound imaging was conducted using the Vevo 3100 25 system equipped with an MS25013–24 MHz transducer (VisualSonics). Imaging was performed to stage pancreatic tumors prior to randomization into treatment groups and to monitor tumor progression biweekly. Tumor volumes were quantified using Vevo LAB analysis software. Migration assay 30 Primary NK cells and CD8⁺ T cells were isolated from the spleens of 8- to 12- week-old female C57BL / 6 mice using the NK Cell Isolation Kit II and CD8a⁺ T Cell Isolation Kit (Miltenyi Biotec), respectively, according to the manufacturer’s instructions. A total of 50,000 NK or CD8⁺ T cells were seeded into the upper 66 Attorney Docket No.07917-0454WO1 / UMMS 24-66 chamber of transwell inserts (Corning) placed in 24-well plates containing serum-free DMEM supplemented with 100 IU / ml penicillin / streptomycin. Serum-free conditioned media collected 24 hours after mRNA treatment of KPC tumor cells was added to the lower chamber. After 4 hours of incubation at 37°C in a humidified 5 incubator with 5% CO₂, migrated cells in the lower chamber were fixed with 4% paraformaldehyde (PFA), stained with DAPI, and quantified using a Celigo imaging cytometer (Nexcelom). Neutralizing antibody studies For NK cell depletion, mice were administered intraperitoneal injections of 10 anti-NK1.1 antibody (250^μg; PK136, BioXcell) twice weekly. For CD8⁺ T cell depletion, mice received intraperitoneal injections of anti-CD8 antibody (200^μg; 2.43, BioXcell) on the same schedule. Effective depletion of NK and CD8⁺ T cells was confirmed by immunohistochemical analysis of pancreatic tumor tissue. Synthesis of LNP-encapsulated mRNA 15 mRNA NPs were synthesized via microfluidic co-flow focusing using a commercially available Fluigent Raydrop. MC3 (48 mol% D-Lin-MC3-DMA, Cayman Chemical) and DSPC (10 mol% 1,2-distearoyl-sn-glycero-3-phosphocholine, Avanti) were prepared in chloroform, along with 37 mol% cholesterol and 5 mol% DMG-PEG (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, 20 Avanti) and formulations were dried overnight to form lipid films. Films were rehydrated in 200 proof ethanol. For microfluidic synthesis, mRNA stocks were diluted in sodium acetate buffer (pH=3) at 20-200 μg / mL and used as the outer aqueous phase and lipids rehydrated in ethanol were used as the inner organic phase in a microfluidic synthesis. The flow rates of the inner and outer phase were set to 12 25 μL / min and 72 μL / min, respectively. Following synthesis, mRNA NPs were dialyzed for 2 h against nuclease-free PBS. Dynamic light scattering (DLS) and zeta potential were used to measure immuno-NP hydrodynamic size and surface, respectively, using a Malvern Zetasizer. A commercially available mRNA detection kit (Quant-it RiboGreen, Invitrogen) was used to analyze loading capacity and encapsulation 30 efficiency following dialysis. 67 Attorney Docket No.07917-0454WO1 / UMMS 24-66 Example 1: Intratumoral delivery of cytokine-encoding mRNA cocktail drove robust local expression of cytokines and chemokines in orthotopic PDAC models. We synthesized mRNAs encoding IL-12, IL-15, IL-18, IFNB1, CXCL10, and CCL5 using our IVT pipeline (FIG. 1A). To enhance translational efficiency in 5 mammalian systems and minimize activation of non-specific innate immune responses, uridine 5′-triphosphate was substituted with N1-methylpseudouridine triphosphate (m¹ΨTP) during IVT, as previously described (28, 29). Conventional IVT reactions often generate double-stranded RNA (dsRNA) byproducts, which can induce the secretion of undesirable proinflammatory cytokines such as IL-6 and are 10 not effectively eliminated by standard lithium chloride (LiCl) precipitation methods. Therefore, to ensure the removal of dsRNA contaminants and generate highly pure mRNA, we utilized a cellulose-based purification strategy (30). We confirmed the successful synthesis of cellulose-purified mRNA on agarose gel. To validate biological activity, the purified mRNAs were transfected into KPC PDAC tumor cell15 lines (KPC1) derived from PDAC tumors in Pdx1-Cre; KrasLSL -G12D / wt;Trp53R172H / wtgenetically engineered mouse models (GEMMs) (31). Lipofectamine transfection of cytokine-encoding mRNA cocktail in vitro revealed a multi-fold increase in levels of all six cytokines / chemokines at 24 h post-transfection (FIG. 8A). Compared to cytokine induction following conventional T / P treatment 20 (FIG. 8B), mRNA transfection achieved significantly higher cytokine expression, highlighting the potential of this approach to augment the pro-inflammatory cytokine milieu in the PDAC TME. Given the prominent abundance of cancer-associated fibroblasts (CAFs) in the PDAC stroma, we further assessed mRNA uptake and translation efficiency in CAFs 25 in vitro. Strikingly, CAFs exhibited even greater secretion of several cytokines and chemokines, including IL-15, IL-18, IFNB1, and CCL5, compared to KPC1 tumor cells (FIGS. 8A and 8C). Following in vitro validation, we orthotopically transplanted KPC1 cell lines into the pancreas of C57BL / 6 female mice. Once tumors in the pancreas were 30 confirmed by ultrasound (10-12 days post-surgery), we administered cytokine- encoding mRNA cocktail (“free” mRNAs) intratumorally and performed cytokine array analysis on the tumor, liver, and blood to ascertain mRNA translation in vivo (FIG. 1B). We saw robust cytokine secretion in the tumors at 24 h, though it was a 68 Attorney Docket No.07917-0454WO1 / UMMS 24-66 transient expression with most cytokines returning to basal levels at 48 h (FIG. 1C). Cytokine profiling of liver and blood indicated a modest increase in systemic CXCL10 and CCL5 levels at 24 hours, while other cytokines remained largely unchanged (FIGS. 1D-1E). Importantly, treatment was well-tolerated, with no 5 significant loss of body weight observed up to 72 hours post-administration (FIG. 1F). Although the six cytokines / chemokines, which were part of the cocktail, lost expression around 48 h, comprehensive cytokine profiling at later timepoints revealed a broader remodeling of the TME. Notably, we saw a significant increase in 10 expression of GM-CSF, a key cytokine involved in dendritic cell maturation and also known to synergize with IL-12 to induce a pro-inflammatory T cell-mediated immune response (32). We also observed an increase in the levels of chemokines MIG (CXCL9), MIP-1α (CCL3), MIP-1β (CCL4), and MIP-2 (CXCL2), which were all critical drivers of NK and T cell recruitment and activation (33) (FIGS. 8D-8E). 15 Additionally, tumors from patients having increased expression in CCL4, CCL5, CXCL9, and CXCL10 exhibited higher abundance of intratumoral CD8+ T cells, and those patients may respond better to PD-1 immunotherapy (34). Together, these findings suggested that intratumoral administration of the cytokine-encoding mRNA cocktail not only augmented local expression of the delivered cytokines but also 20 induced a secondary wave of pro-inflammatory cytokines and chemokines, which could potentially amplify anti-tumor immune effects. To optimize dosing, we compared the effects of 10 µg versus 60 µg of IL-12 mRNA. Although the 60-µg cohort exhibited the highest IL-12 expression, the difference relative to the 10 µg group was not statistically significant (FIG. 8F). 25 Hence, we decided to continue using 10 μg mRNA per cytokine in the remaining studies described herein. Also, we used “free” mRNA (not encapsulated in any carrier) for our studies, thus, we compared 10 μg of “free” IL-12 mRNA with 10 μg of LNP-encapsulated IL-12 mRNA following intratumoral administration. Surprisingly, LNP encapsulation did not confer any benefit in cytokine levels 24 h 30 post mRNA administration in the orthotopic model (FIG. 8G). Finally, we wanted to evaluate what cell types in the PDAC TME can effectively uptake mRNA. Therefore, we synthesized GFP-encoding mRNA and delivered it intratumorally in the KPC1 orthotopic mouse model. Multiplex 69 Attorney Docket No.07917-0454WO1 / UMMS 24-66 immunofluorescence at 6 hours post-administration revealed that GFP expression was predominantly localized to PDPN+fibroblasts, with minimal to no detectable signal in CK19+tumor cells (FIG. 1G). This result also correlated with our in vitro studies, which showed CAFs having significantly higher cytokine expression compared to 5 tumor cells. Example 2: In vitro and in vivo assays revealed distinct roles of individual cytokines and chemokines in facilitating anti-tumor immune effects within the PDAC TME. To rationalize the composition of our mRNA cocktail, we investigated the 10 individual contributions of each cytokine and chemokine to anti-tumor immune activity within the PDAC TME. We began by assessing NK cell migration and activation in vitro. For these assays, KPC1 tumor cells were transfected with individual cytokines and chemokines, as well as various combinations of the cytokine mRNA cocktail, to systematically evaluate their respective roles in NK cell 15 recruitment and activation. After 24 hours, we collected the conditioned media from the transfected cells. NK cells were then isolated from the splenocytes of non-tumor- bearing mice and placed into transwell inserts positioned above the conditioned media to assess their migration. As for the activation assay, isolated NK cells were co- cultured with mRNA transfected KPC1 tumor cells, and NK cell activation was 20 evaluated by measuring the percentage of IFNγ+NK cells using flow cytometry (FIG. 2A). To our surprise, we found that IL-18 and CCL5 were critical for promoting NK cell migration in vitro. Omission of either of these from the combination drastically reduced the number of migrated NK cells. Moreover, none of the individual cytokines or chemokines alone was sufficient to drive significant NK cell migration (FIG. 2B). 25 Similarly, flow cytometry analysis revealed that IL-18 and CCL5 were equally essential for NK cell activation, as the absence of either of these significantly reduced the proportion of IFNγ+NK cells (FIG. 2C). Subsequently, we applied a similar experimental approach to evaluate roles of individual cytokines and chemokines in facilitating CD8+T cell migration and activation (FIG. 2D). Interestingly, none of the 30 cytokines or chemokines demonstrated a strong effect on CD8⁺ T cell migration and combination of four cytokines / chemokines including IL-12, IL-18, IFNB1, and CXCL10 was sufficient to significantly enhance CD8⁺ T cell migration (FIG. 2E). Furthermore, no single cytokine or chemokine was sufficient to promote CD8⁺ T cell 70 Attorney Docket No.07917-0454WO1 / UMMS 24-66 activation. However, various combinations of four, five, or all six cytokines and chemokines effectively enhanced CD8⁺ T cell activation, making it difficult to attribute a distinct role to any single cytokine or chemokine within the cocktail (FIG. 2F). 5 We then investigated the effects of our cytokine mRNA therapy on inducing MHC-I expression on tumor cells in vitro. KPC1 cells were transfected with mRNA cocktail or individual mRNAs (IL-12 / IFNB1), and MHC-I surface expression was assessed by flow cytometry 24 hours post-transfection. IFNB1 is a key mediator of MHC-I upregulation on tumor cells, facilitating enhanced antigen presentation and 10 immune surveillance (35, 36). Similarly, we found that IFNB1 was a critical component of our mRNA cocktail, as it significantly enhanced MHC-I expression on KPC1 cells in vitro. Notably, treatment conditions lacking IFNB1 failed to induce MHC-I upregulation, underscoring its essential role (FIG. 2G). We next evaluated the role of each cytokine and chemokine individually in the15 orthotopic PDAC mouse model. KPC1 tumors were treated with 10 μg of IL-12, IL- 15, IL-18, IFNB1, CXCL10, or CCL5, and tumors were harvested 96 hours after a single dose for flow analysis (FIG. 2H). Surprisingly, our in vivo analysis identified IL-12, IL-15, and CXCL10 as the primary cytokines and chemokines that drove NK cell recruitment, suggesting context-dependent differences from our in vitro findings, 20 where IL-18 and CCL5 played predominant roles (FIG. 2I). However, multiple cytokines and chemokines, including IL-12, IL-18, CXCL10, and CCL5, mediated NK cell cytotoxicity as evidenced by increased expression of granzyme B (GZMB) and IFNγ (FIGS. 2J and 9A). Similar analysis for T cells revealed IL-12 was the major factor for CD8+T cell recruitment, while IL-12, together with CXCL10 and 25 CCL5, promoted CD8⁺ T cell activation (FIGS. 2K-2L and 9B). Further analysis revealed that IL-18 could play a role in CD4⁺ T recruitment, while none of the cytokines or chemokines seemed to effectively activate CD4+T cells (FIGS. 9C-9D). Additionally, other immune populations, including myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs), remained largely unaffected (FIGS. 9E-9F). 30 Collectively, these findings provided the rationale for incorporating most of the cytokines and chemokines into our mRNA cocktail, with the hypothesis that their combined activity was necessary to achieve robust and durable anti-tumor immunity. 71 Attorney Docket No.07917-0454WO1 / UMMS 24-66 Example 3: Intratumoral administration of cytokine-encoding mRNA potentiated anti-tumor immune response and prolonged survival in orthotopic PDAC models. We aimed to investigate the sustained effects of our cytokine mRNA therapy 5 on the PDAC tumor microenvironment (TME). Given the transient nature of cytokine expression following intratumoral mRNA administration (FIG. 1C), we conducted repeated injections of our cytokine mRNA cocktail every three days to enable long- term assessments (FIG. 3A). Reports have highlighted the efficacy of IL-12-encoding mRNA in reshaping the PDAC TME and eliciting anti-tumor immune responses (27, 10 37). Therefore, we conducted a direct comparison between our 6-cytokine mRNA cocktail and IL-12 mRNA monotherapy to determine whether the combined delivery of multiple cytokines and chemokines conferred additional therapeutic benefit. Flow analysis performed after four intratumoral injections of cytokine- encoding mRNA revealed an increase in total immune cell infiltration within the IL- 15 12 mRNA-treated group; notably, this increase was even more pronounced in the group receiving the 6-mRNA cocktail (FIG. 3B). Interestingly, T cell proportions remained largely unchanged, although both treatment groups showed a moderate increase in CD8⁺ and CD4⁺ T cell populations (FIGS. 3C-3D). CD8⁺ T cells exhibited modest activation in both treatment groups, indicated by increased IFNγ expression, 20 although no notable changes were observed in GZMB levels (FIGS. 3E). In contrast, CD4⁺ T cell activation was primarily evident in the 6-mRNA cocktail group, demonstrated by a significantly higher frequency of IFNγ⁺ CD4⁺ T cells, despite no observable differences in GZMB expression (FIG. 10A). Additionally, both treatment groups demonstrated a significant increase in effector memory T cells, whereas an 25 expansion of central memory T cells was observed exclusively in the 6-mRNA cocktail group (FIG. 3F). Furthermore, there were no notable differences in T cell exhaustion markers such as PD-1, CTLA-4, LAG-3, and TIGIT (FIG. 10B). Overall, these findings indicated that cytokine mRNA therapy elicited a modest T cell response, with comparable effects between IL-12 monotherapy and the 6-mRNA30 cocktail, except for a greater expansion of memory T cells observed in the cocktail- treated group. While the 6-mRNA cocktail did not markedly outperform IL-12 monotherapy in enhancing T cell responses, it induced a significantly superior NK cell response. 72 Attorney Docket No.07917-0454WO1 / UMMS 24-66 Specifically, the 6-mRNA cocktail led to significantly greater NK cell recruitment and activation, whereas IL-12 mRNA alone failed to elicit a comparable effect (FIGS. 3G-3H). Differential effects were observed among other immune cell populations, with a modest increase in MDSCs in the 6-mRNA cocktail group, and, interestingly, a 5 pronounced expansion of antigen-presenting dendritic cells (CD103a⁺ DCs) following IL-12 monotherapy (FIGS. 10C-10D). Cancer-associated fibroblasts (CAFs) in the PDAC tumor microenvironment (TME) contributed to an immunosuppressive milieu that restricted the infiltration of cytotoxic NK and T cells critical for effective anti-tumor immunity (38). Therefore, 10 we investigated whether our cytokine mRNA therapy could remodel the fibrotic TME in PDAC. Immunohistochemical analysis revealed a significant reduction of SMA⁺ fibroblasts following IL-12 mRNA monotherapy, with even more pronounced fibroblast clearance observed in tumors treated with the 6-mRNA cocktail (FIGS. 3I- 3J). These results suggested that cytokine mRNA therapy alleviated fibroblast- 15 mediated fibrosis in the PDAC TME, potentially enhancing immune cell infiltration and improving anti-tumor immune responses. Next, we assessed whether our cytokine-encoding mRNA cocktail improved survival outcomes. To this end, we compared our complete 6-mRNA cocktail against IL-12 mRNA monotherapy. All the treatments were administered every 3 days (two 20 times a week) until the end of survival. Ultrasound analysis revealed no significant differences in tumor growth rates in the IL-12 monotherapy group, while the 6- mRNA cocktail group showed modest improvements in tumor growth control (FIG. 3K). Furthermore, long-term survival studies revealed that while the 6-mRNA cocktail group achieved the best survival outcomes, IL-12 monotherapy also 25 improved survival (FIG. 3L). We also evaluated tumor cell proliferation (Ki67) and apoptosis (CC3) by immunohistochemistry. While proliferation rates were comparable across all groups, the IL-12 monotherapy and the 6-mRNA cocktail group exhibited a modest increase in apoptotic cell death (FIG. 10E). To ensure that the observed reduction in tumor volume and CAF abundance in 30 vivo was not a direct consequence of cytokine mRNA uptake and translation, we performed clonogenic assays on KPC1 tumor cells and CAFs in vitro. The results demonstrated that mRNA transfection did not impact tumor cell growth for up to 7 days post-treatment (FIG. 10F). 73 Attorney Docket No.07917-0454WO1 / UMMS 24-66 Together, these results revealed that while intratumoral cytokine-encoding mRNA delivery induced only a modest T cell response, the substantial survival benefit achieved with the 6-mRNA cocktail was driven by markedly enhanced NK cell recruitment and cytotoxicity—an effect not seen with IL-12 monotherapy. 5 Importantly, whereas previous studies in PDAC largely centered on IL-12 mRNA alone, the data provided in the present disclosure established that rationally combining select cytokines and chemokines unlocked a significantly more powerful and durable anti-tumor immune response. Example 4: Neoantigen-driven T cell immunity enhanced the efficacy of cytokine 10 mRNA therapy in PDAC. Recent clinical trials have explored neoantigen-encoding mRNA vaccines as a therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC), demonstrating improved patient survival through the induction of T cell–mediated anti-tumor immunity (39). Longitudinal immune monitoring in vaccine responders revealed that 15 neoantigen-specific T cells remained detectable up to three years post-vaccination, suggesting the establishment of durable immune memory (40). Hence, T cell– enriched pancreatic tumors harboring neoantigens could exhibit an enhanced response to our cytokine mRNA therapy. We orthotopically implanted the KPC 2838 c3 cell line, which exhibited T- 20 cell-high TME (“hot’’ model) and was characterized by the presence of three predicted neoantigens (41). Based on our findings herein, we excluded IL-15 from the mRNA cocktail. In vitro studies demonstrated that the absence of IL-15 did not impede NK or T cell migration or activation (FIGS. 2B, 2C, 2E, and 2F). Furthermore, in vivo analyses indicated that IL-15 contributed only marginally to the 25 recruitment and activation of immune cells (FIGS. 2I-2M). Therefore, all experiments were next conducted using a refined 5-mRNA cocktail comprising IL-12, IL-18, IFNB1, CXCL10, and CCL5. We followed the previously described treatment schedule, administering the mRNA cocktail twice each week with a three-day gap between doses (FIG. 4A).30 Flow cytometry analysis revealed an increase in total immune cell infiltration in the 5- mRNA cocktail group, accompanied by markedly enhanced recruitment of CD8⁺ and CD4⁺ T cells compared to the KPC1 orthotopic model (FIGS. 4B-4D). Moreover, robust T cell activation was observed, driven by strong induction of GZMB 74 Attorney Docket No.07917-0454WO1 / UMMS 24-66 expression. Since GZMB upregulation was dependent on antigen presentation, the presence of three predicted neoantigens likely contributed to more efficient T cell priming and cytotoxic activation in this model (FIGS. 4E-4F). Additionally, we observed pronounced enrichment of effector and central Memory CD8⁺ T Cell 5 populations (FIG. 4G). We also saw an upregulation in PD-1 expression, while other exhaustion markers remained largely unchanged (FIG. 11). Interestingly, administration of the 5-mRNA cocktail failed to substantially increase NK cell recruitment yet resulted in pronounced NK cell activation in this model (FIGS. 4H-4I). As for other immune cell types, while MDSCs were strikingly 10 reduced, there was a significant increase in antigen-presenting dendritic cells (FIGS. 4J-4K). In summary, these data revealed that the presence of tumor neoantigens profoundly amplified the efficacy of cytokine mRNA therapy by promoting robust T cell infiltration, activation, and memory differentiation. This highlighted the 15 synergistic potential of combining cytokine-encoding mRNAs with strategies that enhance tumor-specific T cell priming in PDAC. Example 5: Co-delivery of cytokine- and antigen-encoding mRNAs elicited a comprehensive anti-tumor immune response mediated by cytotoxic T cells and NK cells. 20 Following our studies in the T cell–high ("hot") model, we aimed to investigate a strategy that could elicit a comparable T cell–mediated anti-tumor response in a T cell–low ("cold") TME, such as that of the KPC1 model. To this end, we generated mRNAs encoding three well-characterized tumor-associated antigens— Mesothelin (MSLN), Mucin-1 (MUC1), and Prostate-Specific Membrane Antigen 25 (PSMA)—and combined them with our five-cytokine / chemokine mRNA cocktail (FIG. 5A). We validated the antigen-encoding mRNAs by intratumoral delivery into the KPC1 orthotopic model. Immunohistochemical analysis revealed robust antigen expression at 24 h post-injections (FIG. 5B). To determine if antigen-encoding mRNAs could effectively prime and activate30 T cells, we devised an ex vivo stimulation assay. Splenocytes were isolated from wild- type C57BL / 6 mice and pulsed with antigen-encoding mRNAs for 24 hours. In parallel, T cells were isolated from tumor-bearing mice that had been vaccinated intratumorally with the same antigen-encoding mRNAs 72 hours prior (FIG. 12A). 75 Attorney Docket No.07917-0454WO1 / UMMS 24-66 Antigen-specific activation of T cells from vaccinated tumor-bearing mice was confirmed by a marked increase in IFNγ⁺ GZMB⁺ CD8⁺ T cells following exposure to antigen-mRNA-pulsed splenocytes (FIG. 12B). Therefore, we combined antigen- encoding mRNAs with our cytokine-encoding mRNA cocktail to further assess the 5 anti-tumor immune response in the orthotopic KPC1 mouse model. For immune profiling studies, we followed a similar treatment schedule as previously described (FIG. 5C). The combination of antigen-encoding mRNAs (AM) and cytokine-encoding mRNAs (CM) did not alter total immune cell frequencies, nor did it significantly impact the recruitment of CD8⁺ or CD4⁺ T cells (FIGS. 5D-5E 10 and 12C). However, there was a marked enhancement in CD8⁺ T cell activation with combination therapy, characterized by an elevated GZMB expression—an effect that was notably absent with the cytokine-encoding mRNA cocktail monotherapy treatment arm (FIG. 5F). Most importantly, administration of the antigen-encoding mRNA cocktail alone induced significant T cell activation, highlighting the central 15 role of antigen presence in orchestrating this response. CD4⁺ T cells exhibited only moderate activation as compared to CD8⁺ T cells (FIG. 12D). The memory response mirrored our earlier observations herein, with a significant upregulation of effector and central memory markers in CD8⁺ T cells; however, antigen mRNA treatment did not provide any additional benefit (FIG. 5G). The increase in T cell activation was 20 associated with a concurrent upregulation of multiple exhaustion markers, predominantly in the group treated with the combined cytokine and antigen mRNAs (FIG. 12E). On the contrary, the addition of antigen-encoding mRNAs had a marginal impact on NK cell recruitment or activation, suggesting that the cytokines and25 chemokines within the mRNA cocktail were the principal modulators of NK cell– mediated cytotoxicity (FIGS. 5H-5I). However, antigens promoted a greater expansion of antigen-presenting dendritic cells than cytokines alone, while MDSCs remained largely unchanged (FIGS. 5J and 12F). Overall, a potent anti-tumor immune response resulted in extensive tumor destruction, as was visible by gross 30 histology, with the antigen and cytokine mRNA combination demonstrating the most profound therapeutic effect among all tested conditions (FIG. 5K). In conclusion, combined delivery of cytokine- and antigen-encoding mRNAs elicited a comprehensive anti-tumor immune response. Antigens primarily drove 76 Attorney Docket No.07917-0454WO1 / UMMS 24-66 CD8⁺ T cell activation and expansion of dendritic cells, while cytokines and chemokines promoted NK cell recruitment and cytotoxicity. Collectively, the combination therapy engaged both adaptive and innate immunity, resulting in prominent tumor clearance. 5 Example 6: Single dose of antigen and cytokine mRNA combination therapy sustained tumor control and extended survival in orthotopic models of PDAC. Our prior studies have relied on repeated intratumoral administration of both cytokine- and antigen-encoding mRNAs. However, such a dosing strategy is not clinically practical for PDAC patients. Therefore, for long-term survival studies, we 10 aimed to determine whether a single intratumoral dose of our combination therapy (cytokine + antigen mRNAs) would be sufficient to achieve durable tumor growth control and improve survival outcomes. We first evaluated this strategy in KPC 2838 c3 with T-cell-high (“hot”) TME and three predicted neoantigens (FIG. 6A). Ultrasound imaging performed 14 days 15 following a single intratumoral dose demonstrated significant tumor growth control in the group treated with the 5-mRNA cocktail (FIG. 6B). This early tumor control translated into improved survival outcomes, and indicated that, in the presence of neoantigens, a single administration of cytokine- and chemokine-encoding mRNAs was sufficient to reprogram the PDAC immune microenvironment and drive durable 20 therapeutic benefit (FIG. 6C). Strikingly, even a single intratumoral administration of cytokine and antigen mRNAs was sufficient to overcome immune resistance in the "cold" KPC1 model, resulting in durable tumor control and markedly improved survival (FIGS. 6D–6F). Although a single dose of cytokine mRNAs alone conferred survival benefit, the 25 addition of antigen-encoding mRNAs synergistically augmented the therapeutic response, achieving significantly extended survival (FIG. 6G). These findings highlighted that tumors characterized by a cold immune microenvironment and low mutational burden could be sensitized to immune intervention through the exogenous delivery of well-characterized tumor-associated antigens, particularly when combined 30 with immunostimulatory approaches such as our cytokine mRNA therapy. To confirm that the observed survival outcomes were driven by cytotoxic T and NK cell–mediated anti-tumor immunity, we depleted these immune cell populations using depleting antibodies (FIG. 6H). Depletion of either NK cells or 77 Attorney Docket No.07917-0454WO1 / UMMS 24-66 CD8⁺ T cells abrogated the survival benefit conferred by our cytokine and antigen mRNA therapy, underscoring that the therapeutic efficacy was critically dependent on cytotoxic immune effector mechanisms mediated by these immune cell populations (FIG. 6I). 5 Example 7: LNP-based mRNA delivery significantly curtailed tumor progression in genetically engineered models of PDAC. To further evaluate the therapeutic potential of our combined cytokine- and antigen-encoding mRNAs in a more clinically relevant setting, we expanded our studies into genetically engineered mouse models (GEMMs) of PDAC. Given that 10 GEMMs develop spontaneous tumors that preclude direct intratumoral injection, we encapsulated the mRNAs into LNPs to enable systemic delivery via tail vein injection (FIGS. 13A-13D). Following systemic administration, we performed a comprehensive cytokine array analysis and assessed cytokine secretion profiles across the tumor, liver, and blood (FIG. 7A). Cytokine profiling revealed that expression 15 within tumors was relatively limited at 24 hours post-delivery but markedly increased by 48 hours. In contrast, both blood and liver tissues exhibited robust cytokine expressions at 24 hours, which subsequently declined by 48 hours, suggesting a transient but systemic cytokine surge following LNP-mediated mRNA administration (FIGS. 7B and 13E-113F). However, the maintenance of stable body weights 20 suggested that systemic delivery of LNP-encapsulated mRNAs was well tolerated without inducing measurable off-target toxicities (FIG. 13G). We further confirmed antigen expression within tumor tissues following systemic administration of LNP- formulated mRNAs (FIG. 7C). For immune profiling and survival studies, we adopted a once-weekly dosing 25 schedule of LNP-encapsulated cytokine and antigen mRNAs, based on the observation that systemic cytokine expression necessitated a wider dosing interval (FIG. 7D). Tumors from treated mice demonstrated a substantial expansion of total CD3⁺ T cells, driven by a significant increase in CD8⁺ T cell populations. NK cells were also more abundant, albeit to a lesser extent. Furthermore, there was a notable 30 rise in cytotoxic immune activity, as indicated by elevated GZMB expression (FIGS. 7E-7F). Histopathological examination revealed a striking regression of disease in GEMMs following two doses of combined cytokine and antigen mRNAs, with only 78 Attorney Docket No.07917-0454WO1 / UMMS 24-66 rare residual tumor foci and widespread restoration of benign (PanIN) pancreatic tissue, including extensive areas of normal acinar structures (FIGS. 7G and 13H). Ultrasound analysis further revealed that the combination treatment induced rapid tumor regression, with most tumors markedly reduced by 14 days post-treatment 5 compared to scramble mRNA (i.e., control) (FIG. 7H) and antigen mRNA alone (FIG. 7K). Finally, long-term survival analysis revealed that 4 out of 8 mice treated with the cytokine and antigen combination cocktail achieved a complete response, with no detectable tumors at 60 days following the first dose under a once-weekly dosing 10 regimen. These mice were subsequently taken off treatment at 75 days post-initiation and monitored thereafter for further evaluation of the durability and persistence of the therapeutic response (FIGS. 7I-7J and 7L). Mice treated with either scramble mRNA (i.e., control) or the antigen mRNA cocktail alone failed to survive past day 40 (FIG. 7L). 15 In conclusion, while intratumoral delivery demonstrated therapeutic benefits in orthotopic tumor models, systemic LNP-mediated delivery in GEMMs achieved complete tumor eradication in 50% of treated mice, underscoring both the enhanced efficacy and the clinical practicality of LNP-based administration. References 20 1. L. Rahib et al., Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open 4, e214708 (2021). 2. R. L. Siegel et al., Cancer statistics, 2024. CA Cancer J Clin 74, 12-49 (2024). 3. V. Tonini & M. Zanni, Pancreatic cancer in 2021: What you need to know to win. World J Gastroenterol 27, 5851-5889 (2021).254. M. Ligorio et al., Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer. Cell 178, 160-175 e127 (2019). 5. K. P. Olive et al., Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457-1461 (2009). 6. P. P. Provenzano et al., Enzymatic targeting of the stroma ablates physical barriers to 30 treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418-429 (2012). 7. D. Ohlund et al., Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med 214, 579-596 (2017). 8. N. C. Cheng & R. H. Vonderheide, Immune vulnerabilities of mutant KRAS in pancreatic cancer. Trends Cancer 9, 928-936 (2023). 35 9. M. Ruscetti et al., Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer. Cell 181, 424-441 e421 (2020). 79 Attorney Docket No.07917-0454WO1 / UMMS 24-66 10. J. P. Coppe et al., Senescence-associated secretory phenotypes reveal cell- nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6, 2853-2868 (2008). 11. L. Chibaya et al., EZH2 inhibition remodels the inflammatory senescence-associated 5 secretory phenotype to potentiate pancreatic cancer immune surveillance. Nat Cancer 4, 872- 892 (2023). 12. L. Chibaya et al., Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer. Sci Transl Med 16, eadj9366 (2024). 10 13. C. A. Dinarello, Historical insights into cytokines. Eur J Immunol 37 Suppl 1, S34-45 (2007). 14. C. T. Kureshi & S. K. Dougan, Cytokines in cancer. Cancer Cell 43, 15-35 (2025). 15. S. A. Rosenberg et al., Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant 15 interleukin 2. J Exp Med 161, 1169-1188 (1985). 16. J. M. Kirkwood et al., Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14, 7-17 (1996). 17. M. T. Lotze et al., High-dose recombinant interleukin 2 in the treatment of patients with 20 disseminated cancer. Responses, treatment-related morbidity, and histologic findings. JAMA 256, 3117-3124 (1986). 18. S. A. Rosenberg et al., Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg 228, 307-319 (1998).2519. P. Berraondo et al., Cytokines in clinical cancer immunotherapy. Br J Cancer 120, 6-15 (2019). 20. J. P. Siegel & R. K. Puri, Interleukin-2 toxicity. J Clin Oncol 9, 694-704 (1991). 21. J. Wagstaff et al., A phase I study of recombinant interferon gamma administered by s.c. injection three times per week in patients with solid tumours. Cancer Immunol 30 Immunother 25, 54-58 (1987). 22. R. Kurzrock et al., Pharmacokinetics, single-dose tolerance, and biological activity of recombinant gamma-interferon in cancer patients. Cancer Res 45, 2866-2872 (1985). 23. M. B. Atkins et al., Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res 3, 409-417 (1997). 35 24. S. L. Hewitt et al., Durable anticancer immunity from intratumoral administration of IL-23, IL-36gamma, and OX40L mRNAs. Sci Transl Med 11, (2019). 25. C. Hotz et al., Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models. Sci Transl Med 13, eabc7804 (2021). 40 26. A. E. I. Hamouda et al., Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity. Nat Commun 15, 10635 (2024). 27. A. L. Hughson et al., Integrating IL-12 mRNA nanotechnology with SBRT eliminates T cell exhaustion in preclinical models of pancreatic cancer. Mol Ther Nucleic Acids 35,45102350 (2024). 80 Attorney Docket No.07917-0454WO1 / UMMS 24-66 28. Y. V. Svitkin et al., N1-methyl-pseudouridine in mRNA enhances translation through eIF2alpha-dependent and independent mechanisms by increasing ribosome density. Nucleic Acids Res 45, 6023-6036 (2017). 29. K. Kariko et al., Suppression of RNA recognition by Toll-like receptors: the impact of 5 nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165-175 (2005). 30. M. Baiersdorfer et al., A Facile Method for the Removal of dsRNA Contaminant from In Vitro-Transcribed mRNA. Mol Ther Nucleic Acids 15, 26-35 (2019). 31. S. R. Hingorani et al., Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437-450 (2003). 10 32. E. A. Eksioglu et al., GM-CSF promotes differentiation of human dendritic cells and T lymphocytes toward a predominantly type 1 proinflammatory response. Exp Hematol 35, 1163-1171 (2007). 33. B. G. Dorner et al., MIP-1alpha, MIP-1beta, RANTES, and ATAC / lymphotactin function together with IFN-gamma as type 1 cytokines. Proc Natl Acad Sci U S A 99, 6181- 15 6186 (2002). 34. J. M. Romero et al., A Four-Chemokine Signature Is Associated with a T-cell-Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer. Clin Cancer Res 26, 1997-2010 (2020). 35. S. Wan et al., Chemotherapeutics and radiation stimulate MHC class I expression 20 through elevated interferon-beta signaling in breast cancer cells. PLoS One 7, e32542 (2012). 36. E. Duong et al., Type I interferon activates MHC class I-dressed CD11b(+) conventional dendritic cells to promote protective anti-tumor CD8(+) T cell immunity. Immunity 55, 308-323 e309 (2022). 37. Q. Shen et al., Pancreas-targeted lipid nanoparticles for relatively non-invasive25interleukin-12 mRNA therapy in orthotopic pancreatic ductal adenocarcinoma. J Control Release 381, 113588 (2025). 38. E. Karamitopoulou, Tumour microenvironment of pancreatic cancer: immune landscape is dictated by molecular and histopathological features. Br J Cancer 121, 5-14 (2019). 30 39. L. A. Rojas et al., Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144-150 (2023). 40. Z. Sethna et al., RNA neoantigen vaccines prime long-lived CD8(+) T cells in pancreatic cancer. Nature, (2025). 41. J. Li et al., Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell 35 Infiltration and Response to Immunotherapy. Immunity 49, 178-193 e177 (2018). OTHER EMBODIMENTS It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of40the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 81

Claims

Attorney Docket No.07917-0454WO1 / UMMS 24-66 WHAT IS CLAIMED IS:

1. A composition comprising at least one RNA polynucleotide, wherein the at least one RNA polynucleotide encodes a cytokine polypeptide selected from the group consisting of interleukin 12 (IL-12), interleukin 15 (IL-15), interleukin 18 (IL-18), interferon beta 1 (IFNB1), C-X-C motif chemokine ligand 10 (CXCL10), and C-C motif chemokine ligand 5 (CCL5).

2. The composition of claim 1, wherein the composition comprises: (i) five RNA polynucleotides that encode for the cytokine polypeptides IL-12, IL-18, IFNB1, CXCL10, and CCL5; or (ii) six RNA polynucleotides that encode for the cytokine polypeptides IL- 12, IL-15, IL-18, IFNB1, CXCL10, and CCL5.

3. The composition of claim 1 or 2, wherein the composition comprises at least one RNA polynucleotide that encodes an IL-18 polypeptide, at least one RNA polynucleotide that encodes a CCL5 polypeptide, and at least one RNA polynucleotide that encodes a cytokine polypeptide selected from the group consisting of IL-12, IL-15, IFNB1, and CXCL10.

4. The composition of claim 1 or 2, wherein the composition comprises at least one RNA polynucleotide that encodes an IL-12 polypeptide, at least one RNA polynucleotide that encodes an IL-18 polypeptide, at least one RNA polynucleotide that encodes an IFNB1 polypeptide, at least one RNA polynucleotide that encodes a CXCL10 polypeptide, and at least one RNA polynucleotide that encodes a cytokine polypeptide selected from the group consisting of IL-15 and CCL5.

5. The composition of any one of claims 1-4, wherein the at least one RNA polynucleotide encodes an IL-12A polypeptide, an IL-12B polypeptide or both, optionally wherein the IL-12A polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 1, further optionally 82Attorney Docket No.07917-0454WO1 / UMMS 24-66 wherein the IL-12A polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 1, and / or optionally wherein the IL-12B polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 2, further optionally wherein the IL-12B polypeptide comprises an amino acid sequence that is identical to SEQ ID NO:

2.

6. The composition of any one of claims 1-5, wherein the at least one RNA polynucleotide encodes an IL-18 polypeptide, optionally wherein the IL-18 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 5, further optionally wherein the IL-18 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 5; and / or optionally wherein the IL-18 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 6, further optionally wherein the IL-18 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO:

6.

7. The composition of any one of claims 1-6, wherein the at least one RNA polynucleotide encodes a CCL5 polypeptide, optionally wherein the CCL5 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 7, further optionally wherein the CCL5 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO:

7.

8. The composition of any one of claims 1-7, wherein the at least one RNA polynucleotide encodes a CXCL10 polypeptide, optionally wherein the CXCL10 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 8, further optionally wherein the CXCL10 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO:

8. 83Attorney Docket No.07917-0454WO1 / UMMS 24-66 9. The composition of any one of claims 1-8, wherein the at least one RNA polynucleotide encodes an IFNB1 polypeptide, optionally wherein the IFNB1 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 9, further optionally wherein the IFNB1 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO:

9.

10. The composition of any one of claims 1-9, wherein the at least one RNA polynucleotide encodes an IL-15 polypeptide, optionally wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 3, further optionally wherein the IL-15 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO: 3; and / or optionally wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 4, further optionally wherein the IL-15 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO:

4.

11. The composition of any one of claims 1-10, further comprising at least one RNA polynucleotide that encodes a tumor antigen polypeptide.

12. The composition of claim 11, wherein the least one RNA polynucleotide encodes a tumor antigen polypeptide selected from the group consisting of mesothelin (MSLN), Mucin-1 (Muc1), prostate-specific membrane antigen (PSMA), epidermal growth factor receptor (EGFR), receptor tyrosine kinase like orphan receptor 1 (ROR1), transferrin (TR), carcinoembryonic antigen (CEA), encode tyrosine kinase-type cell surface receptor HER2 (HER2), tumor-associated calcium signal transducer 2 (TROP2), claudin 18.2 (CLDN18.2), mucin-16 (Muc16), prominin-1 (CD133), and cadherin 3 (CDH3), optionally wherein the least one RNA polynucleotide encodes a tumor antigen polypeptide selected from the group consisting of MSLN, Muc1, and PSMA. 84Attorney Docket No.07917-0454WO1 / UMMS 24-66 13. The composition of claim 11 or 12, wherein the composition comprises three RNA polynucleotides that encode for the tumor antigen polypeptides MSLN, Muc1, and PSMA.

14. The composition of any one of claims 11-13, wherein the at least one RNA polynucleotide encodes a MSLN polypeptide, optionally wherein the MSLN polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 10, further optionally wherein the MSLN polypeptide comprises an amino acid sequence that is identical to SEQ ID NO:

10.

15. The composition of any one of claims 11-14, wherein the at least one RNA polynucleotide encodes a Muc1 polypeptide, optionally wherein the Muc1 polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 11, further optionally wherein the Muc1 polypeptide comprises an amino acid sequence that is identical to SEQ ID NO:

11.

16. The composition of any one of claims 11-15, wherein the at least one RNA polynucleotide encodes a PSMA polypeptide, optionally wherein the PSMA polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 12, further optionally wherein the PSMA polypeptide comprises an amino acid sequence that is identical to SEQ ID NO:

12.

17. The composition of any one of claims 1-16, wherein the at least one RNA polynucleotide comprises a messenger RNA (mRNA) polynucleotide.

18. The composition of any one of claims 1-17, wherein the at least one RNA polynucleotide comprises a capped RNA, optionally wherein the RNA polynucleotide is capped using a 7-methylguanosine (m⁷G) cap analog. 85Attorney Docket No.07917-0454WO1 / UMMS 24-66 19. The composition of any one of claims 1-18, wherein the at least one RNA polynucleotide comprises a polyadenylated RNA.

20. The composition of any one of claims 1-19, wherein the at least one RNA comprises at least one modification.

21. The composition of claim 20, wherein the modified RNA comprises at least one modified nucleoside, optionally wherein the at least one modified nucleoside is a uridine nucleoside, further optionally wherein the modified uridine nucleoside is N1-methylpseudouridine-5′-triphosphate.

22. The composition of any one of claims 1-21, wherein the composition comprises less than 5% double-stranded RNA.

23. A pharmaceutical composition comprising the composition of any one of claims 1-22 and a pharmaceutically acceptable carrier.

24. A cancer vaccine comprising the composition of any one of claims 1-22 and a pharmaceutically acceptable carrier, wherein the cancer vaccine optionally comprises an adjuvant.

25. A lipid nanoparticle comprising: at least one phospholipid; at least one PEG lipid; at least one structural lipid; at least one ionizable lipid; and the composition of any one of claims 1-22, preferably wherein the at least one RNA polynucleotide of the composition is encapsulated within the lipid nanoparticle.

26. The lipid nanoparticle of claim 25, wherein: (i) the at least one phospholipid is 1,2-distearoyl-sn-glycero-3- phosphocholine (DSPC); 86Attorney Docket No.07917-0454WO1 / UMMS 24-66 (ii) the at least one PEG lipid 1,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (DMG-PEG); (iii) the at least one structural lipid is cholesterol; and / or (iv) the at least one ionizable lipid is D-Lin-MC3-DMA (MC3).

27. A method of treating cancer in a subject, the method comprising administering a therapeutically effective amount of the composition of any one of claims 1- 22, the pharmaceutical composition of claim 23, the cancer vaccine of claim 24, or the lipid nanoparticle of claim 25 or 26.

28. The method of claim 27, wherein the cancer comprises a cold tumor.

29. The method of claim 27 or 28, wherein the cancer is ovarian cancer, breast cancer, brain cancer, prostate cancer, or pancreatic cancer.

30. The method of claim 29, wherein the pancreatic cancer is selected from the group consisting of pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, adenosquamous carcinoma, colloid carcinoma, and pancreatic neuroendocrine tumors (NETs), optionally wherein the pancreatic cancer is PDAC.

31. The method of any one of claims 27-30, wherein the administering of a composition comprising at least one RNA polynucleotide selected from the group consisting of IL-12, IL-15, IL-18, IFNB1, CXCL10, and CCL5 occurs before, after, or at the same time as the administering of a composition comprising at least one RNA polynucleotide selected from the group consisting of MSLN, Muc1, PSMA, EGFR, ROR1, TR, CEA, HER2, TROP2, CLDN18.2, Muc16, CD133, and CDH3.

32. The method of any one of claims 27-31, wherein the administering is local by intratumoral administration or systemic by intravenous administration. 87

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