Inhibition of NSUN2 for the treatment of cancer

Abstract

The present invention relates generally to the fields of cancer cell biology, cancer therapeutics, immunotherapy and glucose metabolism. More specifically, the invention relates to methods of NSUN2 inhibitors, methods of treating cancer, and methods of reducing cancer resistance to immunotherapy. Also provided are polypeptides, compounds, compositions and combinations for use in reducing resistance to immunotherapy in a cancer cell, reducing oncogenic activity of a cancer cell, inhibiting binding of glucose and NSUN2 in a cell, inhibiting NSUN2 activity in a cell, treating cancer, increasing sensitivity of a cancer cell to immunotherapy, and / or increasing efficacy of immunotherapy in treating cancer.

Description

[0001] Attorney Docket No.9151.272.WO INHIBITION OF NSUN2 FOR THE TREATMENT OF CANCER STATEMENT OF PRIORITY This application claims the benefit of U.S. Provisional Application Serial No. 63 / 513,693, filed July 14, 2023, the entire contents of which are incorporated by reference herein. STATEMENT OF GOVERNMENT SUPPORT This invention was made with government support under Grant Number CA256158 awarded by the National Institutes of Health. The government has certain rights in the invention. STATEMENT REGARDING ELECTRONIC FILING OF A SEQUENCE LISTING A Sequence Listing in XML format, entitled 9151-272WO_ST26.xml, 54,676 bytes in size, generated on July 12, 2024 and filed herewith, is hereby incorporated by reference in its entirety for its disclosures. FIELD OF THE INVENTION The present invention relates generally to the fields of cancer cell biology, cancer therapeutics, immunotherapy and glucose metabolism. More specifically, the invention relates to methods of NSUN2 inhibitors, methods of treating cancer, and methods of reducing cancer resistance to immunotherapy. BACKGROUND OF THE INVENTION Cancers display highly distinct metabolic states compared with normal cells. Enhanced aerobic glycolysis known as Warburg effect is observed in most of cancer types and is associated with cancer stem cell maintenance, cancer progression and metastasis, and drug resistance (Bhattacharya et al., 2016; Dang, 2012; Koppenol et al., 2011; Ward and Thompson, 2012). Glucose is a key nutrient for glycolysis, whose uptake to cancer cells is elevated compared to normal cells partly through increased expression of glucose transporters in cancer cells (Szablewski, 2013). Glucose is thought to act through its metabolism to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Attorney Docket No.9151.272.WO The present invention overcomes previous shortcomings in the art by providing methods and compositions for treating cancers, increasing sensitivity of cancers to immunotherapy, and increasing efficacy of immunotherapy in the treatment of cancers. SUMMARY OF THE INVENTION One aspect of the present invention provides a method of treating cancer in a human subject having or suspected of having cancer, comprising administering to the subject an effective amount of an inhibitor of NSUN2, thereby treating the cancer in the subject. Another aspect of the present invention provides a method of increasing sensitivity of cancer cells to immunotherapy in a human subject having or suspected of having cancer, comprising administering to the subject an effective amount of an inhibitor of NSUN2, thereby increasing sensitivity of the cancer cells to immunotherapy in the subject. Another aspect of the present invention provides a method of increasing efficacy of immunotherapy in treating cancer in a human subject receiving immunotherapy treatment, comprising administering (e.g., co-administering) to the subject receiving immunotherapy treatment an effective amount of an inhibitor of NSUN2. Another aspect of the present invention provides a method of reducing resistance to immunotherapy in a cancer cell, comprising contacting the cell with an effective amount of an inhibitor of NSUN2. Another aspect of the present invention provides a method of reducing oncogenic activity in a cancer cell, comprising contacting the cell with an effective amount of an inhibitor of NSUN2. Another aspect of the present invention provides a method of inhibiting binding of glucose and NSUN2 in a cell, comprising: contacting the cell with an effective amount of a polypeptide comprising an amino acid sequence having at least 90% identity to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33) or a compound, composition or combination comprising the same, thereby inhibiting binding of glucose and NSUN2 in the cell. In some embodiments, the inhibitor of NSUN2 comprises a polypeptide comprising an amino acid sequence having at least 90% identity to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33) or a compound, composition or combination comprising the same. Attorney Docket No.9151.272.WO Another aspect of the present invention provides a compound, composition or combination comprising a polypeptide comprising an amino acid sequence having at least 90% identity to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33). Another aspect of the present invention provides a non-naturally occurring polypeptide (e.g., a synthetic polypeptide) comprising an amino acid sequence having at least 90% identity to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33). Another aspect of the present invention provides a kit comprising the polypeptide, compound, composition or combination of the present invention, and instructions for use. Another aspect of the present invention provides uses of polypeptide, compound, composition or combination of the present invention in reducing resistance to immunotherapy in a cancer cell, reducing oncogenic activity of a cancer cell, reducing Warburg effect in a cancer cell, inhibiting binding of glucose and NSUN2 in a cell, inhibiting NSUN2 activity in a cell, treating cancer, increasing sensitivity of a cancer cell to immunotherapy, and / or increasing efficacy of immunotherapy in treating cancer. Another aspect of the present invention provides preparation of medicaments for use comprising the polypeptide, compound, composition or combination of the present invention. Other and further aspects, features, benefits, and advantages of the present invention will be apparent from the following description of the embodiments of the invention given for the purpose of disclosure. BRIEF DESCRIPTION OF THE DRAWINGS FIG 1 shows images of schematics and gel blots from studies investigating NSUN2 as interacting protein of glucose. FIG.1 panel A: Identification of the potential glucose interacting proteins. Biotin or biotin-glucose was incubated with HEK293 cell lysate, followed by the incubation of streptavidin beads and subjected to mass spectrometry analysis (n = 3 biological replicates). FIG. 1 panels B and C: Immunoblotting of binding complexes isolated from cell extracts of Hep3B (FIG.1 panel B) or PC3 (FIG.1 panel C) incubated with biotin or biotin- glucose (n = 3 biological replicates for each cell line). FIG. 1 panel D: Schematic representations of three NSUN2 isoforms. FIG. 1 panel E: Immunoblotting from in vitro mapping assays among biotin-glucose and NSUN2-F1, NSUN2-F2 or NSUN2-F3 proteins (n = 3 biological replicates). FIG. 1 panel F: Schematic representations of various NSUN2 deletion mutants (NSUN2-Δ1-84, NSUN2-Δ184-190, NSUN2-Δ121-236). FIG. 1 panel G: Attorney Docket No.9151.272.WO Immunoblotting from in vitro mapping assays among biotin-glucose and NSUN2-Δ1-84, NSUN2-Δ184-190, NSUN2-Δ121-236 proteins (n = 3 biological replicates). FIG.1 panel H: Schematic representations of various NSUN2 deletion mutants (NSUN2-Δ1-28, NSUN2-Δ29- 56, NSUN2-Δ57-84. FIG. 1 panel I: Immunoblotting from in vitro mapping assays among biotin-glucose and NSUN2-Δ1-28, NSUN2-Δ29-56, NSUN2-Δ57-84 proteins (n = 3 biological replicates). FIG. 1 panel J: Schematic representations of the sequence for control (GMEGRELGRGKDRAQGRQGDSEARQPRQ; SEQ ID NO: 56) or N28 peptide (MGRRSRGRRLQQQQRPEDAEDGAEGGGK; SEQ ID NO:33) with a TAT tag (YGRKKRRQRRRA; SEQ ID NO:55) in N-terminal region . FIG.1 panel K: Immunoblotting from in vitro pull-down assays by incubating biotin or biotin-glucose directly bind with control or N28 peptide (n = 3 biological replicates). FIG.1 panel L: Immunoblotting from in vitro pull- down assays by incubating biotin or biotin-glucose with NSUN2-F1 protein along with control or N28 peptide. S.E., short exposure; L.E., long exposure (n = 3 biological replicates). See also FIG.8, Table 1 and Table 2. FIG.2 shows images of gel blots and bar graphs from studies examining glucose as a cofactor to directly promote oligomerization and activation of NSUN2. FIG.2 panel A: Hep3B cells without or with glucose starvation for 4 h and restored with glucose (5.5 mM) 2 h before Dot blot assay of m5C levels (total RNA) (n = 3 biological replicates). FIG.2 panel B: Hep3B cells were glucose-starved and restored with glucose, followed by Dot blot assay of m5C levels (n = 3 biological replicates). FIG. 2 panel C: The m5C level intensity of FIG. 2 panel B was determined using ImageJ (n = 3 biological replicates). FIG. 2 panel D: NSUN2 knockdown Hep3B cells were glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h for Dot blot assay (n = 3 biological replicates). FIG. 2 panel E: Hep3B were glucose-starved for 4 h and restored with glucose or 2DG (5.5 mM) 2 h for Dot blot assay (n = 3 biological replicates). FIG.2 panel F: Immunoblotting from in vitro biotin pull-down assays among biotin-2DG and NSUN2-F1 protein (n = 3 biological replicates). FIG.2 panels G and H: Immunoblotting from cell extracts of Hep3B (FIG.2 panel G) or PC3 (FIG.2 panel H) incubated with biotin or biotin- 2DG (n = 3 biological replicates for each cell line). FIG. 2 panels I and J: HK2 knockdown (FIG.2 panel I) and NSUN2 overexpression (FIG.2 panel J) Hep3B cells were glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h for Dot blot assay (n = 3 biological replicates). FIG.2 panel K: Hep3B cells were glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h along with control (6 μM) or N28 (2 μM, 6 μM) peptide treatment for Dot blot assay (n = 3 biological replicates). FIG. 2 panel L: In vitro m5C RNA methylation assays for NSUN2 Attorney Docket No.9151.272.WO activity with various concentrations of glucose (2.75 mM, 5.5 mM, 11 mM, 25 mM) (n = 4 biological replicates). FIG. 2 panel M: In vitro m5C RNA methylation assays for NSUN2 activity with 2DG, glucose or its downstream metabolites (n = 4 biological replicates). FIG.2 panel N: In vitro m5C RNA methylation assays using NSUN2-Δ1-28, NSUN2-Δ29-56 proteins along with or without glucose (n = 4 biological replicates). FIG.2 panel O: In vitro m5C RNA methylation assays using NSUN2 protein along with control or N28 peptide (n = 4 biological replicates). FIG.2 panel P: Native-PAGE assay of NSUN2 protein with various concentrations of glucose (2.75 mM, 5.5 mM, 11 mM, 25 mM) (n = 3 biological replicates). FIG.2 panel Q: Quantification of relative oligomer level of NSUN2 in FIG.2 panel P by normalization with the total level of NSUN2 in SDS-PAGE (n = 3 biological replicates). FIG.2 panel R: Chemical crosslinking of NSUN2 protein with various concentrations of glucose (2.75 mM, 5.5 mM, 11 mM) (n = 3 biological replicates). FIG.2 panels S, T and U: Quantification of relative monomer (FIG. 2 panel S), dimer (FIG. 2 panel T), and oligomer (FIG. 2 panel U) level of NSUN2 in FIG.2 panel R by normalization with the control group of no glucose (Lane 1) (n = 3 biological replicates). FIG. 2 panels V and W: Native-PAGE assay (FIG.2 panel V) and quantification (FIG.2 panel W) of NSUN2, NSUN2-Δ1-28 proteins with or without glucose (5.5 mM). FIG. 2 panels X and Y: Native-PAGE assay (FIG.2 panel X) and quantification (FIG. 2 panel Y) NSUN2 protein along with control or N28 peptide, the relative level of NSUN2 oligomerization in Native-PAGE by normalization with the total level of NSUN2 in SDS- PAGE (n = 3 biological replicates). Data are mean ± SD. *, p < 0.05, **, p < 0.01. ***, p < 0.001, NS, non-significant by Student’s t-test (FIG.2 panels C, L-O, Q, S-U, W, Y). See also FIG.9. FIG. 3 shows images of gel blots and data plots from studies examining Glucose / NSUN2 binding leading to NSUN2 activation and maintenance of oncogenic activity of cancer cells. FIG. 3 panel A: Sphere forming assays of Hep3B cells starved with glucose and restored with various concentrations of glucose (5.5 mM, 11 mM, 25 mM) (n = 3 biological replicates). FIG.3 panel B: Sphere forming assays of Hep3B cells treated with 0 mM glucose, 5.5 mM glucose, 5.5 mM 2DG or 5.5 mM 3OMG (n = 3 biological replicates). FIG.3 panel C: Sphere forming assays in glucose-starved Hep3B cells added back G6P (by transfection) with or without non-metabolizable glucose analog, 2DG or 3OMG (n = 3 biological replicates). FIG. 3 panels D, E, F, and G: Control and NSUN2 knockdown Hep3B cells were subject to immunoblotting (FIG.3 panel D), sphere forming assays (FIG.3 panel E), growth curve (FIG. 3 panel F) and colony forming assays (FIG. 3 panel G) (n = 3 biological replicates). FIG. 3 Attorney Docket No.9151.272.WO panel H: In vivo xenograft tumorigenesis assay of NSUN2 knockdown Hep3B cells subcutaneously injected to nude mice (n = 5 animals / group). FIG.3 panels I, J, and K: Hep3B cells incubated with control or N28 peptide (2 μM, 6 μM) were subjected to sphere forming assays (FIG.3 panel I), growth curve (FIG.3 panel J) and colony forming assays (FIG.3 panel K) (n = 3 biological replicates). FIG. 3 panels L, M, N, O, P, and Q: Control and NSUN2 knockdown Hep3B cells restored with NSUN2-WT or NSUN2-Δ28 were subjected to immunoblotting (FIG.3 panel L), m5C Dot blot assay (FIG.3 panel M), sphere forming assays (FIG.3 panel N), growth curve (FIG.3 panel O), colony forming assays (FIG.3 panel P) and survival rate (FIG.3 panel Q) (n = 3 biological replicates). (FIG.3 panel R) In vivo xenograft tumorigenesis assay of control and NSUN2 knockdown Hep3B cells restored with NSUN2- WT or NSUN2-Δ28 subcutaneously injected to nude mice (n = 5 animals / group). Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t-test (FIG.3 panels A, B, C, E, G, I, K, N, P, Q) or by 2-way ANOVA (FIG.3 panels F, H, J, O, R). See also FIG.10. FIG.4 shows images of blot and data plots from studies examining Glucose / NSUN2 axis maintenance of TREX2 expression to execute its oncogenic activity. FIG.4 panel A: The heatmap for relative mRNA level of selected target genes from RNA-seq in NSUN2 knockdown Hep3B cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). FIG. 4 panels B and C: RT-qPCR analysis (FIG. 4 panel B) and immunoblotting (FIG.4 panel C) in NSUN2 knockdown Hep3B cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). FIG. 4 panel D: Immunoblotting in NSUN2 knockdown Hep3B cells (n = 3 biological replicates). FIG.4 panel E: Immunoblotting in Hep3B cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). FIG. 4 panel F: Immunoblotting in NSUN2 overexpression Hep3B cells (n = 3 biological replicates). FIG. 4 panel G: Immunoblotting in NSUN2 knockdown Hep3B cells restored with NSUN2-WT or NSUN2-Δ28 (n = 3 biological replicates). FIG. 4 panel H: RT-qPCR analysis in the restoration of NSUN2-WT or NSUN2-Δ28 upon NSUN2 knockdown Hep3B cells with or without glucose (5.5 mM) (n = 3 biological replicates). FIG.4 panel I: RNA-IP using anti-m5C antibody, followed by RT-qPCR analysis in the restoration of NSUN2-WT or NSUN2-Δ28 upon NSUN2 knockdown Hep3B cells with or without glucose (5.5 mM) (n = 3 biological replicates). FIG.4 panel J: RNA-IP using anti- m5C antibody, followed by RT-qPCR analysis in Hep3B with glucose starvation for 4 h and restored with glucose (5.5 mM) 2 h along with control or N28 peptide treatment (n = 3 Attorney Docket No.9151.272.WO biological replicates). FIG.4 panel K: Immunoblotting in Hep3B cells, glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h along with control or N28 peptide treatment (n = 3 biological replicates). FIG. 4 panel L: RNA decay assay in the restoration of NSUN2-WT or NSUN2-Δ28 in NSUN2 knockdown Hep3B cells, glucose-starved and restored with glucose (n = 3 biological replicates). FIG.4 panel M: RNA decay assay in NSUN2 overexpression Hep3B cells treated with actinomycin D (Act. D, 2 µg / ml). RT-qPCR against GAPDH was performed to assess the half-life of TREX2 and ACTIN mRNA (n = 3 biological replicates). FIG.4 panel N: RNA-IP using anti-NSUN2 antibody along with various NSUN2 truncated proteins, followed by RT-qPCR analysis of TREX2 mRNA (n = 3 biological replicates). FIG.4 panel O: Schematic representations of mapping assay for the NSUN2 fragment binding to TREX2 mRNA. FIG. 4 panels P, Q, R, and S: Restoration of TREX2 in NSUN2 knockdown Hep3B cells were subjected to immunoblotting (FIG.4 panel P), sphere forming assays (FIG.4 panel Q), colony forming assay (FIG.4 panel R), and survival rate (FIG.4 panel S) (n = 3 biological replicates). FIG.4 panel T: In vivo xenograft tumorigenesis assay of the restoration of TREX2 in NSUN2 knockdown Hep3B subcutaneously inoculated in nude mice (n = 5 animals / group). Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t-test (FIG.4 panels A, B, H-J, N, Q-S) or by 2-way ANOVA (FIG.4 panels L, M, T). See also FIGS.11 and 12, and Table 3. FIG.5 shows images of gel blots, confocal microscopy, data plots, microbial cultures and tissues from studies examining Glucose / NSUN2 / TREX2 Axis restriction of cytosolic dsDNA accumulation for cGAS / STING activation to maintain oncogenic activity of cancer cells. FIG.5 panel A: Immunoblotting in NSUN2 knockdown Hep3B cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). FIG.5 panel B: RT- qPCR analysis in NSUN2 knockdown Hep3B cells restored with NSUN2-WT or NSUN2-Δ28, glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). FIG. 5 panel C: Immunoblotting in NSUN2 knockdown Hep3B cells restored with NSUN2- WT or NSUN2-Δ28 (n = 3 biological replicates). FIG.5 panels D and E: Immunoblotting (FIG. 5 panel D) and RT-qPCR analysis (FIG.5 panel E) in Hep3B cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h along with control or N28 peptide (2 μM) treatment (n = 3 biological replicates). FIG. 5 panels F and G: ELISA (FIG. 5 panel F) and immunoblotting (FIG.5 panel G) in NSUN2 knockdown Hep3B cells restored with or without TREX2 (n = 3 biological replicates). FIG. 5 panel H: Immunoblotting in TREX2 knockdown Hep3B cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). Attorney Docket No.9151.272.WO FIG. 5 panel I: Immunoblotting in Hep3B starved with glucose and restored for 4 h with glucose (5.5 mM) 2 h along with or without cGAMP (1 µM) (n = 3 biological replicates). FIG. 5 panel J: Immunoblotting in shluc, shNSUN2 and shNSUN2+shcGAS Hep3B cells (n = 3 biological replicates). FIG. 5 panel K: RT-qPCR analysis in shluc, shNSUN2, shNSUN2+shSTING and shNSUN2+shcGAS Hep3B cells (n = 3 biological replicates). FIG.5 panels L and M: Confocal images (FIG. 5 panel L) and quantification (FIG. 5 panel M) of cytosolic dsDNA in NSUN2 knockdown Hep3B cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). FIG. 5 panels N and O: Confocal images (FIG. 5 panel N) and quantification (FIG. 5 panel O) of cytosolic dsDNA in Hep3B cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h along with control or N28 peptide (2 μM) treatment. Scale bar, 25 μm (n = 3 biological replicates). FIG.5 panels P, Q, R, and S: Colony forming assays (P), sphere forming assays (FIG.5 panel Q), growth curve (FIG. 5 panel R) and survival rate (FIG. 5 panel S) in shluc, shNSUN2, shNSUN2+shSTING, or shNSUN2+shcGAS Hep3B cells (n = 3 biological replicates). FIG.5 panel T: In vivo xenograft tumorigenesis assays of shluc, shNSUN2, shNSUN2+shSTING and shNSUN2+shcGAS Hep3B cells subcutaneously inoculated in nude mice (n = 5 animals / group). Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t-test (FIG.5 panels B, E, F, K, M, O-Q, S) or by 2-way ANOVA (FIG.5 panels R, T). See also FIGS.13-17. FIG. 6 shows images of tissues, microscopy, and data plots from studies examining Glucose / NSUN2 / TREX2 Axis driven cGAS / STING Signaling Repression leads to Promotion of Anti-PD-L1 Immunotherapy Resistance by Restricting Apoptosis and CD8+T Cell Infiltration. FIG.6 panels A, B, and G-L: Tumor volume (FIG.6 panel A), tumor weight (FIG. 6 panel B), immunohistochemistry for p-STING (FIG.6 panel G), p-TBK1 (FIG.6 panel H), p-IRF3 (FIG.6 panel I), cleaved caspase-3 (FIG.6 panel J), CD3 (FIG.6 panel K), and CD8 (FIG.6 panel L) in vivo allograft tumorigenesis assays of B16 cells overexpression with Vector control, NSUN2-WT or NSUN2-Δ28 inoculated in C57BL / 6 mice (n = 5 animals / group), treated with anti-mouse PD-L1 or rat IgG2b isotype control antibodies. Scale bar, 200 μm. FIG. 6 panels C and D: Tumor volume (FIG.6 panel C) and tumor weight (FIG.6 panel D) in vivo allograft tumorigenesis assays of CT26 cells overexpression with Vector control, NSUN2-WT or NSUN2-Δ28 inoculated in BALB / c mice (n = 5 animals / group), treated with anti-mouse PD- L1 or rat IgG2b isotype control antibodies. FIG.6 panels E and F: Tumor volume (FIG.6 panel E) and tumor weight (FIG.6 panel F) in vivo allograft tumorigenesis assays of Vector+shluc, NSUN2-WT+shluc and NSUN2-WT+shTrex2 B16 cells inoculated in C57BL / 6 mice (n = 5 Attorney Docket No.9151.272.WO animals / group), treated with anti-mouse PD-L1 or rat IgG2b isotype control antibodies. Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t- test (FIG.6 panels B, D, F) or by 2-way ANOVA (FIG.6 panels A, C, E). See also FIG.18. FIG. 7 shows images of tissues, microscopy, data plots and a schematic summary of studies examining the Targeting of Glucose / NSUN2 / TREX2 Axis to overcome Anti-PD-L1 Immunotherapy Resistance through cGAS / STING Activation for Apoptosis and CD8+T Cell Infiltration. FIG.7 panels A, B, E, F, and G: Tumor volume (FIG.7 panel A), tumor weight (FIG. 7 panel B), immunohistochemistry for p-STING (FIG. 7 panel E), cleaved caspase-3 (FIG. 7 panel F), and CD8 (FIG. 7 panel G) in vivo allograft tumorigenesis assays of shluc, shNsun2, shNsun2+shSting, shTrex2, and shTrex2+shSting 4T1 cells injected in BALB / c mice (n = 5 animals / group), treated with anti-mouse PD-L1 or rat IgG2b isotype control antibodies. Scale bar, 50 μm. FIG.7 panels C and D: Tumor volume (FIG.7 panel C) and tumor weight (FIG. 7 panel D) in vivo allograft tumorigenesis assays of shluc, shNsun2, shNsun2+shSting, shTrex2, and shTrex2+shSting TRAMP-C2 cells injected in C57BL / 6 mice (n = 5 animals / group), treated with anti-mouse PD-L1 or rat IgG2b isotype control antibodies. FIG.7 panel H: Illustration of the glucose sensing mechanism by NSUN2, which serves as a glucose sensor whose activation by glucose drives m5C RNA methylation and mRNA stability of TREX2 leading to cGAS / STING repression and subsequent tumor promotion and immunotherapy resistance. Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t-test (FIG.7 panels B, D) or by 2-way ANOVA (FIG.7 panels A, C). See also FIG.19. FIG.8 shows images of blots from studies performed to identify the Potential Glucose Interacting Proteins and Three Isoforms of Recombinant NSUN2 and Various NSUN2 Truncated Proteins Are Purified, Related to FIG 1. (FIG. 8 panel A) Immunoblotting of the binding complexes isolated from cell extracts of HEK293 cells incubated with biotin or biotin- glucose (n = 3 biological replicates). (FIG. 8 panels B and C) Immunoblotting of binding complexes isolated from cell extracts of Hep3B (FIG. 8 panel B) or PC3 (FIG. 8 panel C) incubated with biotin or biotin-glucose (n = 3 biological replicates for each cell line). (FIG.8 panels D, E, and F) The recombinant proteins of three NSUN2 isoforms, NSUN2-F1 (FIG. 8 panel D), NSUN2-F2 (FIG.8 panel E), and NSUN2-F3 (FIG.8 panel F) were expressed in E. coli BL21, cleaved with PreScission protease and purified. The purified recombinant proteins were subjected to SDS-PAGE, followed by Coomassie brilliant blue staining (CBB) and immunoblotting (n = 3 biological replicates). (FIG. 8 panels G, H, and I) Various NSUN2 Attorney Docket No.9151.272.WO truncated protein, NSUN2-Δ1-84, NSUN2-Δ184-190 and NSUN2-Δ121-236 proteins (FIG.8 panel G), NSUN2-Δ1-28, NSUN2-Δ29-56 and NSUN2-Δ57-84 (FIG.8 panel H), NSUN2-F1 and NSUN2-Δ1-28 (FIG. 8 panel I) were cleaved with PreScission protease, purified and verified by CBB and immunoblotting (n = 3 biological replicates). FIG.9 shows images of blots from studies performed to indicating glucose serves as a Cofactor to Directly Promote NSUN2 Activity, Related to FIG. 2. (FIG. 9 panels A and B) Immunoblotting (FIG.9 panel A) and Dot blot assay (FIG.9 panel B) in NSUN2 knockdown Hep3B cells with high glucose (25 mM) (n = 3 biological replicates). (FIG.9 panels C and D) Immunoblotting (FIG.9 panel C) and Dot blot assay (FIG.9 panel D) in NSUN2 knockdown PC3 cells with high glucose (25 mM) (n = 3 biological replicates). (FIG.9 panel E) PC3 cells without or with glucose starvation for 4 h and restored with glucose (5.5 mM) 2 h before Dot blot assay of m5C RNA levels (n = 3 biological replicates). (FIG. 9 panel F) NSUN2 knockdown PC3 cells were glucose-starved and restored with glucose for Dot blot assay (n = 3 biological replicates). (FIG. 9 panel G) PC3 cells were glucose-starved and restored with glucose or 2DG for Dot blot assay (n = 3 biological replicates). (FIG. 9 panels H and I) Immunoblotting of HK2 knockdown Hep3B (FIG.9 panel H) or PC3 (FIG.9 panel I) cells (n = 3 biological replicates for each cell line). (FIG.9 panel J) HK2 knockdown PC3 cells were glucose-starved and restored with glucose for Dot blot assay (n = 3 biological replicates). (FIG. 9 panels K and L) Immunoblotting of NSUN2 overexpression Hep3B (FIG.9 panel K) or PC3 (FIG.9 panel L) cells (n = 3 biological replicates for each cell line). (FIG.9 panel M) NSUN2 overexpression PC3 cells were glucose-starved and restored with glucose for Dot blot assay (n = 3 biological replicates). (FIG.9 panel N) PC3 cells were glucose-starved and restored with glucose along with control (6 μM) or N28 peptide (2 μM, 6 μM) treatment for Dot blot assay (n = 3 biological replicates). FIG.10 shows data plots and images of blots from studies examining Glucose / NSUN2 binding leading to NSUN2 activation and maintenance of oncogenic activity of cancer cells, Related to FIG.3. (FIG.10 panel A) Sphere forming assays of PC3 cells incubated with various concentrations of glucose (5.5 mM, 11 mM, 25 mM) (n = 3 biological replicates). (FIG. 10 panel B) Colony forming assays of Hep3B cells treated with 0 mM glucose, 5.5 mM glucose, 5.5 mM 2DG or 5.5 mM 3OMG (n = 3 biological replicates). (FIG.10 panel C) Colony forming assays in Hep3B cells under glucose deprivation and added back G6P (by transfection) with or without non-metabolizable glucose analog, 2DG or 3OMG (n = 3 biological replicates). (FIG. 10 panels D, E, F, and G) Immunoblotting (FIG.10 panel D), sphere forming assays (FIG.10 Attorney Docket No.9151.272.WO panel E), growth curve (FIG. 10 panel F) and colony forming assays (FIG. 10 panel G) in control and NSUN2 knockdown PC3 cells (n = 3 biological replicates). (FIG.10 panel H) In vivo xenograft tumorigenesis assay of control and NSUN2 knockdown PC3 cells subcutaneously inoculated into nude mice (n = 5 animals / group). (FIG.10 panels I, J, and K) Sphere forming assays (FIG. 10 panel I), growth curve assay (FIG. 10 panel J) and colony forming assay (FIG.10 panel K) in PC3 cells incubated with control or N28 peptide (2 μM, 6 μM) (n = 3 biological replicates). (FIG.10 panel L) ATP assays of Hep3B cells with glucose starvation and restored with glucose along with control or N28 peptide (6 μM) treatment (n = 4 biological replicates). Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non- significant by Student’s t-test (FIG.10 panels A-C, E, G, I, K, L) or by 2-way ANOVA (FIG. 10 panels F, H, J). FIG.11 shows data plots and images of blots from studies examining Glucose / NSUN2 Axis Maintenance of TREX2 Expression in the execution of its oncogenic activity, Related to FIG. 4. (FIG. 11 panels A and B) RT-qPCR analysis mRNA (FIG. 11 panel A) and immunoblotting (FIG. 11 panel B) in control and NSUN2 knockdown Hep3B cells glucose- starved and restored with glucose (n = 3 biological replicates). (FIG. 11 panel C) Immunoblotting in Hep3B cells glucose-starved and restored with glucose (n = 3 biological replicates). (FIG.11 panel D) Immunoblotting in control and NSUN2 knockdown Hep3B cells (n = 3 biological replicates). (FIG. 11 panel E) Immunoblotting in control and NSUN2 knockdown PC3 cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). (FIG. 11 panel F) Immunoblotting in control and NSUN2 knockdown PC3 cells (n = 3 biological replicates). (FIG. 11 panel G) Immunoblotting in control and NSUN2 overexpression PC3 cells (n = 3 biological replicates). (FIG. 11 panel H) m5C RNA methylation levels in control and NSUN2 knockdown Hep3B cells glucose-starved and restored with glucose (n = 3 biological replicates). (FIG. 11 panel I) RT-qPCR analysis of TREX2 mRNA expression in control and NSUN2 overexpression Hep3B cells (n = 3 biological replicates). (FIG.11 panel J) RNA-IP using anti-m5C antibody, followed by RT-qPCR analysis m5C level of TREX2 mRNA in PC3 cells with or without glucose (n = 3 biological replicates). (FIG.11 panel K) RT-qPCR analysis of TREX2 mRNA in PC3 cells with or without glucose (n = 3 biological replicates). (FIG.11 panel L) RNA-IP using anti-m5C antibody, followed by RT-qPCR analysis m5C level of TREX2 mRNA in control and NSUN2 knockdown PC3 cells with or without glucose (n = 3 biological replicates). (FIG.11 panel M) RT-qPCR analysis of TREX2 mRNA expression in control and NSUN2 knockdown PC3 cells with or without Attorney Docket No.9151.272.WO glucose (n = 3 biological replicates). (FIG. 11 panel N) RNA decay assay in NSUN2 knockdown PC3 cells treated with actinomycin D (Act. D, 2 µg / ml). RT-qPCR against GAPDH was performed to assess the half-life of TREX2 and ACTIN mRNA (n = 3 biological replicates). (FIG. 11 panel O) RNA decay assay in control and NSUN2 overexpression PC3 cells (n = 3 biological replicates). (FIG. 11 panel P) RNA-IP using anti-NSUN2 antibody along with various NSUN2 truncated proteins (n = 3 biological replicates). (FIG.11 panel Q) Restoration of TREX2 in NSUN2 knockdown Hep3B cells were subjected to growth curve assay (n = 3 biological replicates). Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non- significant by Student’s t-test (FIG.11 panels A, H-M, P) or by 2-way ANOVA (FIG.11 panels N, O, Q). FIG.12 shows data plots and images of blots from studies examining Glucose / NSUN2 Axis Fails to Affect mRNA and Protein Expression of TREX1; and TREX2 Knockdown Impairs Oncogenic Activity of Cancer Cells, Related to FIG. 4. (FIG.12 panel A) RT-qPCR analysis of TREX1 mRNA expression in control and NSUN2 overexpression Hep3B cells (n = 3 biological replicates). (FIG. 12 panels B and C) RT-qPCR analysis of TREX1 mRNA in Hep3B (FIG.12 panel B) or PC3 cells (FIG.12 panel C) glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). (FIG. 12 panel D and E) Immunoblotting in Hep3B (FIG.12 panel D) or PC3 cells (FIG.12 panel E) glucose-starved and restored with glucose (n = 3 biological replicates). (FIG. 12 panels F and G) Immunoblotting in control and NSUN2 knockdown Hep3B (FIG.12 panel F) or PC3 (FIG.12 panel G) cells (n = 3 biological replicates). (FIG.12 panel H) Immunoblotting in control and NSUN2 overexpression Hep3B cells (n = 3 biological replicates). (FIG.12 panels I, J, K, L, and M) Immunoblotting (FIG. 12 panel I), sphere forming assays (FIG. 12 panel J), growth curve (FIG.12 panel K), colony forming assays (FIG.12 panel L) and survival rate (FIG.12 panel M) in TREX2 knockdown Hep3B cells (n = 3 biological replicates). Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t-test (FIG.12 panels A-C, J, L, M) or by 2-way ANOVA (FIG.12 panel K). FIG. 13 shows data plots and images of blots from studies examining Glucose / NSUN / TREX2 axis restriction of cGAS / STING activation, Related to FIG.5. (FIG. 13 panels A, B, C, D and E) ELISA (FIG.13 panels A and D), immunoblotting (FIG.13 panel B), RT-qPCR analysis (FIG. 13 panels C and E) in TREX2 knockdown Hep3B cells (n = 3 biological replicates). ( FIG. 13 panels F and G) ELISA in Hep3B (FIG.13 panel F) or PC3 (FIG. 13 panel G) cells without or with glucose starvation for 4 h and restored with glucose Attorney Docket No.9151.272.WO (5.5 mM) 2 h (n = 3 biological replicates for each cell line). (FIG. 13 panels H and I) Immunoblotting in Hep3B (FIG. 13 panel H) or PC3 (FIG. 13 panel I) cells without or with glucose starvation for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates for each cell line). ( FIG. 13 panels J, K, and L) Immunoblotting in Hep3B cells without or with glucose starvation for 4 h and restored with 5.5 mM 2DG (FIG.13 panel J), 3OMG (FIG. 13 panel K), G6P (by transfection) (FIG. 13 panel L) for 2 h (n = 3 biological replicates). ( FIG.13 panels M, N and O) RT-qPCR analysis (FIG.13 panels M and O) and ELISA (FIG. 13 panel N) in Hep3B cells glucose-starved and restored with glucose (n = 3 biological replicates). (FIG. 13 panels P and Q) RT-qPCR analysis (FIG. 13 panel P, n = 3 biological replicates) and ELISA (FIG. 13 panel Q, n = 4 biological replicates) in PC3 cells glucose- starved and restored with glucose. (FIG.13 panel R) ELISA in control and NSUN2 knockdown PC3 cells (n = 3 biological replicates). (FIG.13 panels S and T) ELISA (FIG.13 panel S) and RT-qPCR analysis (FIG. 13 panel T) in control and NSUN2 knockdown Hep3B cells (n = 3 biological replicates). (FIG. 13 panel U) Immunoblotting in control and NSUN2 knockdown PC3 cells (n = 3 biological replicates). (FIG.13 panels V and W) Immunoblotting (V) and RT- qPCR analysis (W) in control and NSUN2 knockdown PC3 cells glucose-starved and restored with glucose (n = 3 biological replicates). (FIG. 13 panel X) RT-qPCR analysis of IFN-β expression in control and NSUN2 knockdown Hep3B cells restored with or without TREX2 (n = 3 biological replicates). Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t-test (FIG.13 panels A, C-G, M-T, W, X). FIG. 14 shows data plots and images of blots from studies examining Glucose / NSUN / TREX2 axis restriction of cGAS / STING activation, Related to FIG.5. (FIG. 14 panels A and B) Immunoblotting (FIG.14 panel A) and RT-qPCR analysis (FIG.14 panel B) in control, NSUN2 overexpression Hep3B cells (n = 3 biological replicates). (FIG.14 panels C and D) Immunoblotting (FIG. 14 panel C) and RT-qPCR analysis (FIG. 14 panel D) in control, TREX2 overexpression Hep3B cells (n = 3 biological replicates). (FIG. 14 panel E) Immunoblotting in Hep3B with or without cGAMP (1 µM) (n = 3 biological replicates).(FIG. 14 panels F and G) Immunoblotting in cGAS knockdown (FIG. 14 panel F) or STING knockdown (FIG.14 panel G) Hep3B cells (n = 3 biological replicates). (FIG.14 panels H and I) Immunoblotting in cGAS knockdown (FIG. 14 panel H) or STING knockdown (FIG. 14 panel I) Hep3B cells glucose-starved and restored with glucose (n = 3 biological replicates). (FIG. 14 panel J) Immunoblotting in shluc, shNSUN2, and shNSUN2+shSTING Hep3B cells (n = 3 biological replicates). (FIG. 14 panel K) Immunoblotting in Hep3B without or with Attorney Docket No.9151.272.WO glucose starvation, or along with AMPK inhibitor compound C (CC, 10 µM) treatment for 6 h (n = 3 biological replicates). (FIG.14 panel L) Immunoblotting in AMPK deficiency MEF cells without or with glucose starvation for 4 h and restored with glucose (5.5 mM) for 2 h (n = 3 biological replicates). Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non- significant by Student’s t-test (FIG.14 panels B, D). FIG. 15 shows data plots and microscopy images from studies determining that the Glucose / NSUN2 / TREX2 axis restricts cytosolic dsDNA accumulation, Related to FIG. 5. (FIG.15 panels A and B) Confocal images (FIG.15 panel A) and quantification (FIG.15 panel B) of cytosolic dsDNA in Hep3B cells without or with glucose starvation for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). (FIG. 15 panels C and D) Confocal images (FIG.15 panel C) and quantification (FIG.15 panel D) of cytosolic ssDNA in Hep3B cells without or with glucose starvation for 4 h and restored with glucose (5.5 mM) for 2 h (n = 3 biological replicates). (FIG. 15 panels E and F) Confocal images (FIG. 15 panel E) and quantification (FIG. 15 panel F) of cytosolic dsDNA in NSUN2 knockdown Hep3B cells restored with NSUN2-WT or NSUN2-Δ28 with high glucose (25 mM) (n = 3 biological replicates). (FIG. 15 panels G and H) Confocal images (FIG. 15 panel G) and quantification (FIG.15 panel H) of cytosolic dsDNA in shluc, shTREX2, shTREX1, or shTREX1+shTREX2 Hep3B cells with high glucose (25 mM) (n = 3 biological replicates). (FIG.15 panels I and J) Confocal images (FIG.15 panel I) and quantification (FIG.15 panel J) of cytosolic dsDNA in control and NSUN2 knockdown PC3 cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). Scale bar, 25 μm. Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t-test (FIG.15 panels B, D, F, H, J). FIG. 16 shows data plots and microscopy images from studies examining TREX2 serving as a downstream effector of Glucose / NSUN2 axis to restrict cytosolic dsDNA accumulation, Related to FIG.5. (FIG.16 panels A and B) Confocal images (FIG.16 panel A) and quantification (FIG.16 panel B) of TREX2 in control and TREX2 knockdown Hep3B cells (n = 3 biological replicates). (FIG.16 panels C and D) Confocal images (FIG.16 panel C) and quantification (FIG.16 panel D) of cytosolic dsDNA in control and TREX2 knockdown Hep3B cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). (FIG. 16 panels E and F) Confocal images (FIG. 16 panel E) and quantification (FIG.16 panel F) of cytosolic dsDNA in PC3 cells glucose-starved and restored with glucose along with control or N28 peptide (2 μM) treatment (n = 3 biological replicates). (FIG. 16 Attorney Docket No.9151.272.WO panels G and H) Confocal images (FIG.16 panel G) and quantification (FIG.16 panel H) of cytosolic dsDNA in control and TREX2 overexpression Hep3B cells glucose-starved and restored for 4 h with glucose (5.5 mM) 2 h (n = 3 biological replicates). (FIG.16 panels I and J) Confocal images (FIG.16 panel I) and quantification (FIG.16 panel J) of cytosolic dsDNA in control and NSUN2 knockdown Hep3B cells restored with TREX2, glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). Scale bar, 25 μm. Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t- test (FIG.16 panels B, D, F, H, J). FIG.17 shows data plots and images of blots from studies determining that cGAS or STING knockdown promoted cancer cell proliferation, survival and cancer stemness, Related to FIG.5. (FIG.17 panel A) Immunoblotting of control and TREX2 knockdown Hep3B cells (n = 3 biological replicates). (FIG. 17 panel B) Immunoblotting of in shluc, shTREX2, shTREX1, or shTREX1+shTREX2 Hep3B cells (n = 3 biological replicates). (FIG.17 panel C) Immunoblotting of control and TREX2 knockdown Hep3B cells glucose-starved for 4 h and restored with glucose (5.5 mM) 2 h (n = 3 biological replicates). (FIG. 17 panels D and E) Sphere forming assays in control, cGAS knockdown (FIG. 17 panel D), and STING knockdown (FIG.17 panel E) Hep3B cells (n = 3 biological replicates). (FIG.17 panels F and G) Growth curve in control, cGAS knockdown (FIG. 17 panel F), and STING knockdown (FIG.17 panel G) Hep3B cells (n = 3 biological replicates). (FIG.17 panels H and I) Colony forming assays in control, cGAS knockdown (FIG.17 panel H), and STING knockdown (FIG. 17 panel I) Hep3B cells (n = 3 biological replicates). Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t-test (FIG.17 panels D, E, H, I) or by 2-way ANOVA (FIG.17 panels F, G). FIG. 18 shows data plots and images of blots from studies identifying that the Glucose / NSUN2 / TREX2 axis drives cGAS / STING signaling repression and anti-PD-L1 immunotherapy resistance by restricting apoptosis and CD8+T cell infiltration, Related to FIG. 6. (FIG.18 panels A and B) Immunoblotting of B16 (FIG.18 panel A) and CT26 cells (FIG. 18 panel B) overexpression with Vector control, NSUN2-WT or NSUN2-Δ28 (n = 3 biological replicates for each cell line). (FIG. 18 panels C and D) Immunoblotting of Vector+shluc, NSUN2-WT+shluc and NSUN2-WT+shTrex2 in B16 (FIG.18 panel C) and CT26 cells (FIG. 18 panel D) (n = 3 biological replicates for each cell line). (FIG. 18 panels E and F) Tumor volume (FIG.18 panel E) and tumor weight (FIG.18 panel F) in vivo allograft tumorigenesis of Vector+shluc, NSUN2-WT+shluc and NSUN2-WT+shTrex2 CT26 cells injected in BALB / c Attorney Docket No.9151.272.WO mice (n = 5 animals / group), treated with anti-mouse PD-L1 or rat IgG2b isotype control antibodies. (FIG.18 panel G) Quantification of immunohistochemistry for p-STING, p-TBK1, p-IRF3, cleaved caspase-3, CD3, and CD8 in vivo allograft tumorigenesis assays of B16 cells overexpression with Vector control, NSUN2-WT or NSUN2-Δ28 inoculated in C57BL / 6 mice (n = 5 animals / group), treated with anti-mouse PD-L1 or rat IgG2b isotype control antibodies. Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t-test (FIG.18 panels F, G) or by 2-way ANOVA (FIG.18 panel E). FIG. 19 shows data plots and images of blots, and microscopy images from studies determining that the targeting Glucose / NSUN2 / TREX2 Axis overcomes anti-PD-L1 immunotherapy resistance through cGAS / STING activation for apoptosis and CD8+T cell infiltration, Related to FIG 7. (FIG.19 panels A and B) Immunoblotting of control and NSUN2 knockdown in 4T1 (FIG.19 panel A) and TRAMP-C2 cells (FIG.19 panel B) (n = 3 biological replicates for each cell line). (FIG.19 panels C and D) Immunoblotting of control and TREX2 knockdown in 4T1 (FIG.19 panel C) and TRAMP-C2 cells (FIG.19 panel D) (n = 3 biological replicates for each cell line). (FIG.19 panels E and F) Immunoblotting of control and STING knockdown in 4T1 (FIG. 19 panel E) and TRAMP-C2 (FIG. 19 panel F) (n = 3 biological replicates for each cell line). (FIG. 19 panels G and H) Immunoblotting of shluc, shNsun2, shNsun2+shSting in 4T1 (FIG.19 panel G) and TRAMP-C2 (FIG.19 panel H) (n = 3 biological replicates for each cell line). (FIG. 19 panels I and J) Immunoblotting of shluc, shTrex2, shTrex2+shSting in 4T1 (FIG.19 panel I) and TRAMP-C2 (FIG.19 panel J) (n = 3 biological replicates for each cell line). (FIG.19 panels K, L, and M) Immunohistochemistry for p-TBK1 (FIG. 19 panel K), p-IRF3 (FIG. 19 panel L), and CD3 (FIG. 19 panel M) in vivo allograft tumorigenesis assays of shluc, shNsun2, shNsun2+shSting, shTrex2, and shTrex2+shSting 4T1 cells inoculated in BALB / c mice (n = 5 animals / group), treated with anti-mouse PD-L1 or rat IgG2b isotype control antibodies. Scale bar, 50 μm. (FIG. 19 panel N) Quantification of immunohistochemistry for p-STING, p-TBK1, p-IRF3, cleaved caspase-3, CD3, and CD8 in vivo allograft tumorigenesis assays of shluc, shNsun2, shNsun2+shSting, shTrex2, and shTrex2+shSting 4T1 cells injected in BALB / c mice (n = 5 animals / group), treated with anti- mouse PD-L1 or rat IgG2b isotype control antibodies. Data are mean ± SD. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, non-significant by Student’s t-test (N). DETAILED DESCRIPTION OF THE INVENTION The present invention now will be described hereinafter with reference to the Attorney Docket No.9151.272.WO accompanying drawings and examples, in which embodiments of the invention are shown. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. Thus, the invention contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention. Hence, the following descriptions are intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations, and variations thereof. 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. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and / or paragraph in which the reference is presented. Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a composition comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination. Definitions As used in the description of the invention and the appended claims, the singular forms "a," "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also as used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or"). Attorney Docket No.9151.272.WO The term "about" as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified value as well as the specified value. For example, "about X" where X is the measurable value, is meant to include X as well as variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of X. A range provided herein for a measurable value may include any other range and / or individual value therein. As used herein, phrases such as "between X and Y" and "between about X and Y" should be interpreted to include X and Y. As used herein, phrases such as "between about X and Y" mean "between about X and about Y" and phrases such as "from about X to Y" mean "from about X to about Y." Also, as used herein, "one or more" means one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc. The term "comprise," "comprises" and "comprising" as used herein, specify the presence of the stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. As used herein, the transitional phrase "consisting essentially of" means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. Thus, the term "consisting essentially of" when used in a claim of this invention is not intended to be interpreted to be equivalent to "comprising."   The term "consists essentially of" (and grammatical variants), as applied to a polynucleotide or polypeptide sequence of this invention, means a polynucleotide or polypeptide that consists of both the recited sequence (e.g., SEQ ID NO) and a total of ten or less (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) additional nucleotides or amino acids on the 5’ and / or 3’ or N-terminal and / or C-terminal ends of the recited sequence or between the two ends (e.g., between domains) such that the function of the polynucleotide or polypeptide is not materially altered. The total of ten or less additional nucleotides or amino acids includes the total number of additional nucleotides or amino acids added together. The term "materially altered," as applied to polynucleotides of the invention, refers to an increase or decrease in ability to express the encoded polypeptide of at least about 50% or more as compared to the expression level of a polynucleotide consisting of the recited sequence. The term "materially altered," as applied to polypeptides of the invention, refers to an increase or decrease in biological activity of at Attorney Docket No.9151.272.WO least about 50% or more as compared to the activity of a polypeptide consisting of the recited sequence. Amino acids are represented herein in the manner recommended by the IUPAC-IUB Biochemical Nomenclature Commission, or (for amino acids) by either the one-letter code, or the three letter code, both in accordance with 37 C.F.R. §1.822 and established usage. As used herein, the term "amino acid" encompasses any naturally occurring amino acids, modified forms thereof, and synthetic amino acids, including non-naturally occurring amino acids. Alternatively, the amino acid can be a modified amino acid residue or can be an amino acid that is modified by post-translation modification (e.g., acetylation, amidation, formylation, hydroxylation, methylation, phosphorylation or sulfatation). Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate further, if, for example, the specification indicates that a particular amino acid can be selected from A, G, I, L and / or V, this language also indicates that the amino acid can be selected from any subset of these amino acid(s) for example A, G, I or L; A, G, I or V; A or G; only L; etc., as if each such subcombination is expressly set forth herein. Moreover, such language also indicates that one or more of the specified amino acids can be disclaimed. For example, in particular embodiments the amino acid is not A, G or I; is not A; is not G or V; etc., as if each such possible disclaimer is expressly set forth herein. As used herein, the term "polypeptide" encompasses both peptides and proteins, unless indicated otherwise. A "polynucleotide," "nucleic acid," or "nucleic acid molecule" as used herein is a sequence of nucleotide bases, and may be RNA, DNA or DNA-RNA hybrid sequences (including both naturally occurring and non-naturally occurring nucleotide), but in representative embodiments are either single or double stranded DNA sequences. As used herein, an "isolated" polynucleotide (e.g., an "isolated DNA" or an "isolated RNA") means a polynucleotide at least partially separated from at least some of the other components of the naturally occurring organism or virus, for example, the cell or viral structural components or other polypeptides or nucleic acids commonly found associated with the polynucleotide. In representative embodiments an "isolated" nucleotide is enriched by at Attorney Docket No.9151.272.WO least about 10-fold, 100-fold, 1000-fold, 10,000-fold or more as compared with the starting material. Likewise, an "isolated" polypeptide means a polypeptide that is at least partially separated from at least some of the other components of the naturally occurring organism or virus, for example, the cell or viral structural components or other polypeptides or nucleic acids commonly found associated with the polypeptide. In representative embodiments an "isolated" polypeptide is enriched by at least about 10-fold, 100-fold, 1000-fold, 10,000-fold or more as compared with the starting material. As used herein, by "isolate" or "purify" (or grammatical equivalents) a vector, it is meant that the vector (e.g., a virus vector, e.g., an expression vector, e.g., a liposome, etc.) is at least partially separated from at least some of the other components in the starting material. In representative embodiments an "isolated" or "purified" vector is enriched by at least about 10-fold, 100-fold, 1000-fold, 10,000-fold or more as compared with the starting material. A "therapeutic polypeptide" is a polypeptide or peptide that can alleviate, reduce, prevent, delay and / or stabilize symptoms that result from an absence or defect in a protein in a cell or subject and / or is a polypeptide that otherwise confers a benefit to a subject. "Amino acid sequence" and terms such as "peptide," "polypeptide," and "protein" are used interchangeably herein, and are not meant to limit the amino acid sequence to the complete, native amino acid sequence (i.e., a sequence containing only those amino acids found in the protein as it occurs in nature) associated with the recited protein molecule. The proteins and protein fragments of the presently disclosed subject matter can be produced by recombinant approaches or can be isolated from a naturally occurring source. The protein fragments can be any size, and for example can range in size from four amino acid residues to the entire amino acid sequence minus one amino acid. The term "sequence identity," as used herein, has the standard meaning in the art. As is known in the art, a number of different programs can be used to identify whether a polynucleotide or polypeptide has sequence identity or similarity to a known sequence. Sequence identity or similarity may be determined using standard techniques known in the art, including, but not limited to, the local sequence identity algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the sequence identity alignment algorithm of Needleman & Wunsch, J. Mol. Biol.48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Natl. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Attorney Docket No.9151.272.WO Package, Genetics Computer Group, 575 Science Drive, Madison, WI), the Best Fit sequence program described by Devereux et al., Nucl. Acid Res. 12:387 (1984), preferably using the default settings, or by inspection. An example of a useful algorithm is PILEUP. PILEUP creates a multiple sequence alignment from a group of related sequences using progressive, pairwise alignments. It can also plot a tree showing the clustering relationships used to create the alignment. PILEUP uses a simplification of the progressive alignment method of Feng & Doolittle, J. Mol. Evol.35:351 (1987); the method is similar to that described by Higgins & Sharp, CABIOS 5:151 (1989). Another example of a useful algorithm is the BLAST algorithm, described in Altschul et al., J. Mol. Biol. 215:403 (1990) and Karlin et al., Proc. Natl. Acad. Sci. USA 90:5873 (1993). A particularly useful BLAST program is the WU-BLAST-2 program which was obtained from Altschul et al., Meth. Enzymol., 266:460 (1996); blast.wustl / edu / blast / README.html. WU-BLAST-2 uses several search parameters, which are preferably set to the default values. The parameters are dynamic values and are established by the program itself depending upon the composition of the particular sequence and composition of the particular database against which the sequence of interest is being searched; however, the values may be adjusted to increase sensitivity. An additional useful algorithm is gapped BLAST as reported by Altschul et al., Nucleic Acids Res.25:3389 (1997). A percentage amino acid sequence identity value is determined by the number of matching identical residues divided by the total number of residues of the "longer" sequence in the aligned region. The "longer" sequence is the one having the most actual residues in the aligned region (gaps introduced by WU-Blast-2 to maximize the alignment score are ignored). In a similar manner, percent nucleic acid sequence identity is defined as the percentage of nucleotide residues in the candidate sequence that are identical with the nucleotides in the polynucleotide specifically disclosed herein. The alignment may include the introduction of gaps in the sequences to be aligned. In addition, for sequences which contain either more or fewer nucleotides than the polynucleotides specifically disclosed herein, it is understood that in one embodiment, the percentage of sequence identity will be determined based on the number of identical nucleotides in relation to the total number of nucleotides. Thus, for example, sequence identity of sequences shorter than a sequence specifically disclosed herein, will be determined using the number of nucleotides in the shorter sequence, in one embodiment. In percent identity Attorney Docket No.9151.272.WO calculations relative weight is not assigned to various manifestations of sequence variation, such as insertions, deletions, substitutions, etc. In one embodiment, only identities are scored positively (+1) and all forms of sequence variation including gaps are assigned a value of "0," which obviates the need for a weighted scale or parameters as described below for sequence similarity calculations. Percent sequence identity can be calculated, for example, by dividing the number of matching identical residues by the total number of residues of the "shorter" sequence in the aligned region and multiplying by 100. The "longer" sequence is the one having the most actual residues in the aligned region. As used herein, an "isolated" nucleic acid or nucleotide sequence (e.g., an "isolated DNA" or an "isolated RNA") means a nucleic acid or nucleotide sequence separated or substantially free from at least some of the other components of the naturally occurring organism or virus, for example, the cell or viral structural components or other polypeptides or nucleic acids commonly found associated with the nucleic acid or nucleotide sequence. Likewise, an "isolated" polypeptide means a polypeptide that is separated or substantially free from at least some of the other components of the naturally occurring organism or virus, for example, the cell or viral structural components or other polypeptides or nucleic acids commonly found associated with the polypeptide. As used herein, the term "modified," as applied to a polynucleotide or polypeptide sequence, refers to a sequence that differs from a native / wildtype sequence due to one or more deletions, additions, substitutions, or any combination thereof. A "heterologous nucleotide sequence" or "heterologous nucleic acid," with respect to a cell, is a sequence or nucleic acid, respectively, that is not naturally occurring in the cell. Generally, the heterologous nucleic acid or nucleotide sequence comprises an open reading frame that encodes a polypeptide and / or a nontranslated RNA. The term "fragment," as applied to a peptide, will be understood to mean an amino acid sequence of reduced length relative to a reference peptide or amino acid sequence and comprising, consisting essentially of, and / or consisting of an amino acid sequence of contiguous amino acids identical to the reference peptide or amino acid sequence. Such a peptide fragment according to the invention may be, where appropriate, included in a larger polypeptide of which it is a constituent. In some embodiments, such fragments can comprise, consist essentially of, and / or consist of peptides having a length of at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more consecutive amino acids of a peptide or amino acid sequence according to the invention. In other embodiments, such fragments can comprise, consist essentially of, and / or consist of peptides Attorney Docket No.9151.272.WO having a length of less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or less consecutive amino acids of a peptide or amino acid sequence according to the invention. As used herein, the terms "protein" and "polypeptide" are used interchangeably and encompass both peptides and proteins, unless indicated otherwise. The "N-terminus" of a polypeptide is any portion of the polypeptide that starts from the N-terminal amino acid residue and continues to a maximum of the midpoint of the polypeptide. The "C-terminus" of a polypeptide is any portion of the polypeptide that starts from the C-terminal amino acid residue and continues to a maximum of the midpoint of the polypeptide. As used herein, a "functional" peptide or "functional fragment" is one that substantially retains at least one biological activity normally associated with that peptide (e.g., binding to or inhibiting a calcium channel). In particular embodiments, the "functional" peptide or "functional fragment" substantially retains all of the activities possessed by the unmodified peptide. By "substantially retains" biological activity, it is meant that the peptide retains at least about 50%, 60%, 75%, 85%, 90%, 95%, 97%, 98%, 99%, or more, of the biological activity of the native polypeptide (and can even have a higher level of activity than the native peptide). A "non- functional" peptide is one that exhibits little or essentially no detectable biological activity normally associated with the peptide (e.g., at most, only an insignificant amount, e.g., less than about 10% or even 5%). Biological activities such as protein binding and calcium channel inhibitory activity can be measured using assays that are well known in the art and as described herein. A "fusion protein" is a polypeptide produced when two heterologous nucleotide sequences or fragments thereof coding for two (or more) different polypeptides not found fused together in nature are fused together in the correct translational reading frame. Illustrative fusion polypeptides include fusions of a peptide of the invention (or a fragment thereof) to all or a portion of glutathione-S-transferase, maltose-binding protein, or a reporter protein (e.g., Green Fluorescent Protein, ^-glucuronidase, ^-galactosidase, luciferase, etc.), hemagglutinin, c-myc, FLAG epitope, etc. As used herein, "nucleic acid molecule," "nucleotide sequence," and "polynucleotide" are used interchangeably and encompass both RNA and DNA, including cDNA, genomic DNA, mRNA, synthetic (e.g., chemically synthesized) DNA or RNA and chimeras of RNA and DNA. The term nucleic acid refers to a chain of nucleotides without regard to length of the chain. The nucleic acid can be double-stranded or single-stranded. Where single-stranded, the nucleic acid can be a sense strand or an antisense strand. The nucleic acid can be synthesized Attorney Docket No.9151.272.WO using oligonucleotide analogs or derivatives (e.g., inosine or phosphorothioate nucleotides). Such oligonucleotides can be used, for example, to prepare nucleic acids that have altered base- pairing abilities or increased resistance to nucleases. The present invention further provides a nucleic acid that is the complement (which can be either a full complement or a partial complement) of a nucleic acid or nucleotide sequence of this invention. An "isolated polynucleotide" is a nucleotide sequence (e.g., DNA or RNA) that is not immediately contiguous with nucleotide sequences with which it is immediately contiguous (one on the 5' end and one on the 3' end) in the naturally occurring genome of the organism from which it is derived. Thus, in one embodiment, an isolated nucleic acid includes some or all of the 5' non-coding (e.g., promoter) sequences that are immediately contiguous to a coding sequence. The term therefore includes, for example, a recombinant DNA that is incorporated into a vector, into an autonomously replicating plasmid or virus, or into the genomic DNA of a prokaryote or eukaryote, or which exists as a separate molecule (e.g., a cDNA or a genomic DNA fragment produced by PCR or restriction endonuclease treatment), independent of other sequences. It also includes a recombinant DNA that is part of a hybrid nucleic acid encoding an additional polypeptide or peptide sequence. An isolated polynucleotide that includes a gene is not a fragment of a chromosome that includes such gene, but rather includes the coding region and regulatory regions associated with the gene, but no additional genes naturally found on the chromosome. A "recombinant" nucleic acid, polynucleotide or nucleotide sequence is one produced by genetic engineering techniques. A "recombinant" polypeptide is produced from a recombinant nucleic acid, polypeptide or nucleotide sequence. A polypeptide, composition, compound or combination of the invention may be chimeric, meaning that at least one of its components is heterologous with respect to at least one of its other components (e.g., a promoter from the host organism operably linked to a polynucleotide of interest to be expressed in the host organism, wherein the polynucleotide of interest is from a different organism than the host or is not normally found in association with that promoter). The term "isolated" can refer to a nucleic acid, nucleotide sequence or polypeptide that is substantially free of cellular material, viral material, and / or culture medium (when produced by recombinant DNA techniques), or chemical precursors or other chemicals (when chemically synthesized). Moreover, an "isolated fragment" is a fragment of a nucleic acid, nucleotide Attorney Docket No.9151.272.WO sequence or polypeptide that is not naturally occurring as a fragment and would not be found in the natural state. "Isolated" does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to provide the polypeptide or nucleic acid in a form in which it can be used for the intended purpose. An isolated cell refers to a cell that is separated from other components with which it is normally associated in its natural state. For example, an isolated cell can be a cell in culture medium and / or a cell in a pharmaceutically acceptable carrier of this invention. Thus, an isolated cell can be delivered to and / or introduced into a subject. In some embodiments, an isolated cell can be a cell that is removed from a subject and manipulated as described herein ex vivo and then returned to the subject. A "vector" is any nucleic acid molecule for the cloning of and / or transfer of a nucleic acid into a cell. A vector may be a replicon to which another nucleotide sequence may be attached to allow for replication of the attached nucleotide sequence. A "replicon" can be any genetic element (e.g., plasmid, phage, cosmid, chromosome, viral genome) that functions as an autonomous unit of nucleic acid replication in vivo, i.e., capable of replication under its own control. The term "vector" includes both viral and nonviral (e.g., plasmid) nucleic acid molecules for introducing a nucleic acid into a cell in vitro, ex vivo, and / or in vivo. A large number of vectors known in the art may be used to manipulate nucleic acids, incorporate response elements and promoters into genes, etc. For example, the insertion of the nucleic acid fragments corresponding to response elements and promoters into a suitable vector can be accomplished by ligating the appropriate nucleic acid fragments into a chosen vector that has complementary cohesive termini. Alternatively, the ends of the nucleic acid molecules may be enzymatically modified or any site may be produced by ligating nucleotide sequences (linkers) to the nucleic acid termini. Such vectors may be engineered to contain sequences encoding selectable markers that provide for the selection of cells that contain the vector and / or have incorporated the nucleic acid of the vector into the cellular genome. Such markers allow identification and / or selection of host cells that incorporate and express the proteins encoded by the marker. A "recombinant" vector refers to a viral or non-viral vector that comprises one or more heterologous nucleotide sequences (i.e., transgenes), e.g., two, three, four, five or more heterologous nucleotide sequences. Viral vectors have been used in a wide variety of gene delivery applications in cells, as well as living animal subjects. Viral vectors that can be used include, but are not limited to, retrovirus, lentivirus, adeno-associated virus, poxvirus, alphavirus, baculovirus, vaccinia virus, Attorney Docket No.9151.272.WO herpes virus, Epstein-Barr virus, and adenovirus vectors. Non-viral vectors include plasmids, liposomes, electrically charged lipids (cytofectins), nucleic acid-protein complexes, and biopolymers. In addition to a nucleic acid of interest, a vector may also comprise one or more regulatory regions, and / or selectable markers useful in selecting, measuring, and monitoring nucleic acid transfer results (delivery to specific tissues, duration of expression, etc.). Vectors may be introduced into the desired cells by methods known in the art, e.g., transfection, electroporation, microinjection, transduction, cell fusion, DEAE dextran, calcium phosphate precipitation, lipofection (lysosome fusion), use of a gene gun, or a nucleic acid vector transporter (see, e.g., Wu et al., J. Biol. Chem.267:963 (1992); Wu et al., J. Biol. Chem. 263:14621 (1988); and Hartmut et al., Canadian Patent Application No.2,012,311, filed Mar. 15, 1990). In various embodiments, other molecules can be used for facilitating delivery of a nucleic acid in vivo, such as a cationic oligopeptide (e.g., WO95 / 21931), peptides derived from nucleic acid binding proteins (e.g., WO96 / 25508), and / or a cationic polymer (e.g., WO95 / 21931). It is also possible to introduce a vector in vivo as naked nucleic acid (see U.S. Patent Nos. 5,693,622, 5,589,466 and 5,580,859). Receptor-mediated nucleic acid delivery approaches can also be used (Curiel et al., Hum. Gene Ther.3:147 (1992); Wu et al., J. Biol. Chem.262:4429 (1987)). The term "transfection" or "transduction" means the uptake of exogenous or heterologous nucleic acid (RNA and / or DNA) by a cell. A cell has been "transfected" or "transduced" with an exogenous or heterologous nucleic acid when such nucleic acid has been introduced or delivered inside the cell. A cell has been "transformed" by exogenous or heterologous nucleic acid when the transfected or transduced nucleic acid imparts a phenotypic change in the cell and / or a change in an activity or function of the cell. The transforming nucleic acid can be integrated (covalently linked) into chromosomal DNA making up the genome of the cell or it can be present as a stable plasmid. By the term "express" or "expression" of a polynucleotide coding sequence, it is meant that the sequence is transcribed, and optionally, translated. Typically, according to the present invention, expression of a coding sequence of the invention will result in production of the polypeptide of the invention. The entire expressed polypeptide can also function in intact cells without purification. "Label" or "tag" as used herein may be any suitable label or detectable or otherwise functional group, e.g., a detectable moiety, including but not limited to biotin, avidin, Attorney Docket No.9151.272.WO fluorophores, antigens (including proteins and peptides), antibodies, porphyrins, radioactive or stable isotopes, etc., inclusive of examples as further described herein. "Linker" or "linking group" as used herein may be any suitable linking group, including but not limited to groups comprising, consisting of or consisting essentially of C, O, N, P and / or S (e.g., including H where necessary). Linking groups that may be used to form covalent conjugates of two functional moieties are known in the art. See, e.g., US Patents Nos. 6,420,377; 6,593,334; and 6,624,317. The specific linking group employed will depend upon the particular synthetic method used to make the covalent conjugate, as will be appreciated by those skilled in the art. A suitable linking group will permit the joining of groups to provide a metabolically stable conjugate. In general, the linking moiety may comprise an aliphatic, aromatic, or mixed aliphatic and aromatic group (e.g., alkyl, aryl, alkylaryl, etc.) and contain one or more amino acids or hetero atoms such as N, O, S, etc. The terms "antibody" and "immunoglobulin" include antibodies or immunoglobulins of any isotype, fragments of antibodies that retain specific binding to antigen, including but not limited to Fab, Fv, single chain Fv (scFv), Fc, and Fd fragments, chimeric antibodies, humanized antibodies, single-chain antibodies, and fusion proteins including an antigen- binding portion of an antibody and a non-antibody protein. The antibodies can in some embodiments be detectably labeled, e.g., with a radioisotope, an enzyme which generates a detectable product, a fluorescent protein, and the like. The antibodies can in some embodiments be further conjugated to other moieties, such as members of specific binding pairs, e.g., biotin (member of biotin-avidin specific binding pair), and the like. Also encompassed by the terms are Fab', Fv, F(ab')2, and other antibody fragments that retain specific binding to antigen (e.g., any antibody fragment that comprises at least one paratope). Antibodies can exist in a variety of other forms including, for example, Fv, Fab, and (Fab')2, as well as bi-functional (i.e., bi-specific) hybrid antibodies (see e.g., Lanzavecchia et al., 1987) and in single chains (see e.g., Huston et al., 1988 and Bird et al., 1988, each of which is incorporated herein by reference in its entirety). See generally, Hood et al., 1984, and Hunkapiller & Hood, 1986. The phrase "detection molecule" is used herein in its broadest sense to include any molecule that can bind with sufficient specificity to a biomarker to allow for detection of the particular biomarker. To allow for detection can mean to determine the presence or absence of the particular biomarker member and, in some embodiments, can mean to determine the amount of the particular biomarker. Detection molecules can include antibodies, antibody fragments, and nucleic acid sequences. Attorney Docket No.9151.272.WO The term "contact" or grammatical variations thereof as used with respect to the interaction between two or more components, e.g., NSUN2 and an inhibitor thereof, e.g., NSUN2 and glucose, e.g., an inhibitor of NSUN2 and a cell, refers to bringing the two components in sufficiently close proximity to each other for one to exert a biological effect on the other. In some embodiments, the term contact means binding of the one component to the other. The term "modulate," "modulates," or "modulation" refers to enhancement (e.g., an increase) or inhibition (e.g., a decrease) in the specified level or activity. By "substantially retain" a property, it is meant that at least about 75%, 85%, 90%, 95%, 97%, 98%, 99% or 100% of the property (e.g., activity or other measurable characteristic) is retained. As used herein, the terms "increase," "increases," "increased," "increasing," "improve," "enhance," and similar terms indicate an elevation in the specified parameter of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500% or more. As used herein, the terms "reduce," "reduces," "reduced," "reduction," "inhibit," and similar terms refer to a decrease in the specified parameter of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100%. As used herein, the term "therapeutically effective amount" or "effective amount" can refer to that amount of a pharmaceutical composition that results in amelioration of symptoms (e.g., reduction in size or elimination of a tumor) and / or a prolongation of survival in a subject. A therapeutically relevant effect relieves to some extent one or more symptoms of a disease or condition or returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or condition. As used herein, the terms "treating" or "treatment" of a condition or disease can include: (1) inhibiting the disease or condition, i.e., arresting, delaying or reducing the development of the disease or condition and its symptoms; or (2) relieving the disease or condition, i.e., causing regression of the disease or condition and its clinical symptoms. The term "treatment" or "treating," as used herein, does not encompass 100% cure of cancer. However, in one embodiment, the therapeutic methods described herein can result in 100% reversal of detectable disease. As used herein, the terms "prophylactic" or "preventative" treatment can include preventing at least one symptom of the disorder, disease or condition, i.e., causing a clinical Attorney Docket No.9151.272.WO symptom to not significantly develop in a subject that may develop or be predisposed to the disease but does not yet experience or display symptoms of the disease or condition. The terms "prevent," "preventing" and "prevention" (and grammatical variations thereof) refer to prevention and / or delay of the onset of a disease, disorder and / or a clinical symptom(s) in a subject and / or a reduction in the severity of the onset of the disease, disorder and / or clinical symptom(s) relative to what would occur in the absence of the methods of the invention. The prevention can be complete, e.g., the total absence of the disease, disorder and / or clinical symptom(s). The prevention can also be partial, such that the occurrence of the disease, disorder and / or clinical symptom(s) in the subject and / or the severity of onset is less than what would occur in the absence of the present invention. As used herein, the terms "subject" and "patient" are used interchangeably herein and refer to both human and nonhuman animals. A subject of this invention can be any subject that is susceptible to a disorder that can benefit by the methods and compositions of the present invention and / or be treated for a disorder by the methods and compositions of the present invention. In some embodiments, the subject of any of the methods of the present invention is a mammal. The term "mammal" as used herein includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, and the like), etc. Human subjects include neonates, infants, juveniles, and adults. As a further option, the subject can be a laboratory animal and / or an animal model of disease. Preferably, the subject is a human. The subject may be of any gender, any ethnicity and any age. A "subject in need thereof" or "a subject in need of" is a subject known to have, or is suspected of having or developing or is at risk of having or developing disorder that can be treated by the methods and compositions of the present invention, or would benefit from the delivery of a particle and / or composition including those described herein. The term "administering" or "administered" as used herein is meant to include topical, parenteral and / or oral administration, all of which are described herein. Parenteral administration includes, without limitation, intravenous, subcutaneous and / or intramuscular administration (e.g., skeletal muscle or cardiac muscle administration). It will be appreciated that the actual method and order of administration will vary according to, inter alia, the particular preparation of compound(s) being utilized, and the particular formulation(s) of the one or more other compounds being utilized. The optimal method and order of administration of the compositions of the invention for a given set of conditions can be ascertained by those Attorney Docket No.9151.272.WO skilled in the art using conventional techniques and in view of the information set out herein. The term "administering" or "administered" also refers, without limitation, to oral, sublingual, buccal, transnasal, transdermal, rectal, intramuscular, intravenous, intraarterial (intracoronary), intraventricular, intrathecal, and subcutaneous routes. In accordance with good clinical practice, the instant compounds can be administered at a dose that will produce effective beneficial effects without causing undue harmful or untoward side effects, i.e., the benefits associated with administration outweigh the detrimental effects. In some embodiments, more than one administration (e.g., two, three, four or more administrations) by one or more same and / or different routes of administration, may be employed to achieve the desired level of effect (e.g., a therapeutically effective amount) over a period of various intervals, e.g., daily, weekly, monthly, yearly, etc. Also as used herein, the terms "treat," "treating" or "treatment" refer to any type of action that imparts a modulating effect, which, for example, can be a beneficial and / or therapeutic effect, to a subject afflicted with a condition, disorder, disease or illness, including, for example, improvement in the condition of the subject (e.g., in one or more symptoms), delay in the progression of the disorder, disease or illness, and / or change in clinical parameters of the condition, disorder, disease or illness, etc., as would be well known in the art. Additionally as used herein, the terms "proactive," "prevent," "preventing" or "prevention" refer to any type of action that results in the absence, avoidance and / or delay of the onset and / or progression of a disease, disorder and / or a clinical symptom(s) in a subject and / or a reduction in the severity of the onset of the disease, disorder and / or clinical symptom(s) relative to what would occur in the absence of the methods of the invention. The prevention can be complete, e.g., the total absence of the disease, disorder and / or clinical symptom(s). The prevention can also be partial, such that the occurrence of the disease, disorder and / or clinical symptom(s) in the subject and / or the severity of onset is less than what would occur in the absence of the present invention. An "effective amount" or "therapeutically effective amount" refers to an amount of a compound or composition of this invention that is sufficient to produce a desired effect, which can be a therapeutic and / or beneficial effect. In general, a "therapeutically effective amount" or "treatment effective amount" refers to an amount that is a sufficient, but non-toxic, amount of the active ingredient (i.e., particles of this invention) to achieve the desired effect, which, for example, can be a reduction or elimination in the severity and / or frequency of symptoms and / or improvement or remediation of damage, or otherwise prevent, hinder, retard or reverse Attorney Docket No.9151.272.WO the progression of a disease or any other undesirable symptom. The effective amount will vary with the age, general condition of the subject, the severity of the condition being treated, the particular agent administered, the duration of the treatment, the nature of any concurrent treatment, the pharmaceutically acceptable carrier used, and like factors within the knowledge and expertise of those skilled in the art. As appropriate, an effective amount or therapeutically effective amount in any individual case can be determined by one of ordinary skill in the art by reference to the pertinent texts and literature and / or by using routine experimentation. (See, for example, Remington, The Science and Practice of Pharmacy (latest edition)). The term "biologically active" as used herein means an enzyme or protein having structural, regulatory, or biochemical functions of a naturally occurring molecule. Methods and compositions All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. All compositions described herein may be useful in the methods described herein and / or other useful utility such as reagents for in vitro and / or in vivo research and development. Cancers display highly distinct metabolic states compared with normal cells. Enhanced aerobic glycolysis known as Warburg effect is observed in most cancer types and is associated with cancer stem cell maintenance, cancer progression and metastasis, and drug resistance (Bhattacharya et al., 2016; Dang, 2012; Koppenol et al., 2011; Ward and Thompson, 2012). Glucose is a key nutrient for glycolysis, whose uptake to cancer cells is elevated compared to normal cells partly through increased expression of glucose transporters in cancer cells (Szablewski, 2013). Hexokinase (HK) is a rate limiting enzyme mediating the first step of glycolysis for tumorigenesis (Hay, 2016). While not wishing to be bound to theory, glucose metabolism through glycolysis is thought to provide key energy sources and also building blocks and redox homeostasis for cancer cells proliferation and survival leading to cancer progression (Cairns et al., 2011; Hay, 2016). Glucose not only serves as a critical nutrient to fuel cancer growth and survival through glycolysis and TCA cycle (Lee, 2014), but also drives global histone H3 acetylation to regulate its oncogenic activity through acetyl-CoA production (Friis et al., 2009; Ladurner, 2009; Rathmell and Newgard, 2009; Wellen et al., 2009) and histone H3 Attorney Docket No.9151.272.WO ubiquitination (Zhang et al., 2017). These studies helped establish an understanding in the field that glucose may maintain its oncogenic activity primarily through glucose metabolism. A study b y Bandyopadhyay et al. indicated that glucose could trigger mitogen-activated protein kinase activation in adipocytes in a manner which may be independent of glucose metabolism (Bandyopadhyay et al., 2000). However, it has remain unclear whether glucose can also act as a signaling molecule that directly binds to its target proteins for maintaining oncogenic processes independently of glucose metabolism. This invention is based, in part, on the discovery by the inventors that glucose is a binding cofactor to methyltransferase NOP2 / Sun RNA Methyltransferase 2 ("NSUN2", also known as Misu (Myc-induced SUN-domain-containing protein), MRT5, SAKI, or TRM4). Without wishing to be bound to theory, the inventors of the invention found that glucose binds to NSUN2 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation including TREX2 exonuclease ("Three Prime Repair Exonuclease 2"), and stabilizes TREX2 to perform activities including restricting cytosolic dsDNA accumulation and cyclic GMP-AMP synthase – Stimulator of Interferon Genes ("cGAS / STING") pathway activation, leading to the promotion of tumorigenesis and anti-PD- L1 immunotherapy resistance. A NSUN2 mutant defective in glucose binding and / or disrupting glucose / NSUN2 interaction abolished NSUN2 activity and TREX2 induction, leading to cGAS / STING activation and impaired oncogenic processes. Genetic deletion of the glucose / NSUN2 / TREX2 axis suppressed tumorigenesis and overcame anti-PD-L1 immunotherapy resistance in cold tumors through cGAS / STING activation, facilitating cancer cell apoptosis and CD8+T cell infiltration into the tumor and / or tumor microenvironment. These discoveries offer a strategy to target cancer without impacting normal glucose metabolism. As used herein, the term "cGAS / STING" refers to the innate immune system cytosolic DNA sensing pathway and the components thereof. The cGAS / STING pathway is a component pathway of intracellular defense mechanisms which functions to detect the presence of cytosolic DNA and initiate expression of responsive inflammatory genes, proteins, and other innate intracellular defense mechanisms against, for example, infection of the cell. Expression or activity of cGAS / STING may include, but is not limited to, the expression and / or activity of STING protein, cGAS protein, and / or downstream intermediary and effector components. The role of the cGAS / STING pathway in cellular defense mechanisms and in various disorders and Attorney Docket No.9151.272.WO diseases is further described in Decout et al., 2021 Nature Reviews Immunology 21(548-569), the disclosures of which are incorporated herein by reference. Thus, one aspect of the present invention provides a method of reducing resistance to immunotherapy in a cancer cell, comprising contacting the cell with an effective amount of an inhibitor of NSUN2. Another aspect of the present invention provides a method of reducing oncogenic activity in a cancer cell, comprising contacting the cell with an effective amount of an inhibitor of NSUN2. In some embodiments, the oncogenic activity of the cancer cell may comprise, but is not limited to, Warburg effect, cancer stem cell maintenance, cancer cell proliferation, and / or cancer treatment resistance (such as e.g., resistance to immunotherapy). As used herein, the term "inhibitor" and similar terms refers to a molecule (e.g., small molecule, e.g., a compound, e.g., a nucleic acid molecule, e.g., a polypeptide) that interferes with expression and / or any activity of the listed target. As such, the term "inhibitor of NSUN2" refers a molecule that interferes with the expression and / or activity of NSUN2. Non-limiting examples of an inhibitor of NSUN2 include an inhibitor of NSUN2 expression, an inhibitor of NSUN2 activation, an inhibitor of NSUN2 activity, and / or an inhibitor of NSUN2 binding by glucose. In some embodiments, wherein the inhibitor of NSUN2 comprises a polypeptide comprising an amino acid sequence having at least about 70% sequence identity (e.g., at least about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% sequence identity or any value or range therein) to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33) or a compound, composition or combination comprising the same. In some embodiments, the inhibitor of NSUN2 comprises the amino acid sequence RRSR (SEQ ID NO:34). In some embodiments, the contacting of the cancer cell with the inhibitor of NSUN2 may inhibit NSUN2 activity in the cancer cell, e.g., inhibits NSUN2 activity in the cancer cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein) as compared to a control, for example, a cancer cell not contacted with the inhibitor. Attorney Docket No.9151.272.WO In some embodiments, the contacting of the cancer cell with the inhibitor of NSUN2 may reduce TREX2 expression and / or activity in the cancer cell, e.g., reduces TREX2 expression and / or activity in the cancer cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein) as compared to a control, for example, a cancer cell not contacted with the inhibitor. In some embodiments, the contacting of the cancer cell with the inhibitor of NSUN2 may enhance cGAS / STING expression and / or activity in the cancer cell, e.g., enhances cGAS / STING expression and / or activity in the cancer cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more or any value or range therein) as compared to a control, for example, a cancer cell not contacted with the inhibitor. In some embodiments, the contacting of the cancer cell with the inhibitor of NSUN2 does not affect glucose metabolism of the cancer cell, e.g., wherein normal glucose metabolism is substantially retained. In some embodiments, the contacting of the cancer cell with the inhibitor of NSUN2 minimally affects glucose metabolism, e.g., does not substantially effect glucose metabolism as compared to control, for example, normal glucose metabolism in a non- cancerous or cancerous cell. In some embodiments of the methods of the present invention, the cancer cell may be in a subject, e.g., a mammalian subject, e.g., a human subject, e.g., a patient. In some embodiments, the cancer cell may be an in vitro cell, an ex vivo cell, or an in vivo cell. Another aspect of the present invention provides a method of inhibiting binding of glucose and NSUN2 in a cell, comprising: contacting the cell with an effective amount of a polypeptide comprising an amino acid sequence having at least 70% sequence identity (e.g., at least about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% sequence identity or any value or range therein) to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33) or a compound, composition or combination comprising the same, thereby inhibiting binding of glucose and NSUN2 in the cell. In some embodiments, the contacting of the cell with the polypeptide or compound, composition or combination comprising the same may inhibit NSUN2 expression and / or activity in the cell , e.g., inhibits NSUN2 activity in the cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, Attorney Docket No.9151.272.WO 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein) as compared to a control, for example, a cell not contacted with the polypeptide or compound, composition or combination. In some embodiments, the contacting of the cell with the polypeptide or compound, composition or combination comprising the same may reduce TREX2 expression and / or activity in the cell, e.g., reduces TREX2 expression and / or activity in the cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein), as compared to a control, for example, a cell not contacted with the polypeptide or compound, composition or combination. In some embodiments, the contacting of the cell with the polypeptide or compound, composition or combination comprising the same may enhance cGAS / STING expression and / or activity in the cell, e.g., enhances cGAS / STING expression and / or activity in the cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein), as compared to a control, for example, a cell not contacted with the polypeptide or compound, composition or combination. In some embodiments, the cell may be a cancer cell. In some embodiments, the cell may be an in vitro cell, an ex vivo cell, or an in vivo cell. In some embodiments, the cell may be in a subject, e.g., a mammalian subject, e.g., a human subject, e.g., a patient. Another aspect of the present invention provides a method of treating cancer in a human subject having or suspected of having cancer (e.g., a patient), comprising administering to the subject an effective amount of an inhibitor of NSUN2, thereby treating the cancer in the subject. Another aspect of the present invention provides a method of increasing sensitivity of cancer cells to immunotherapy in a human subject having or suspected of having cancer, comprising administering to the subject an effective amount of an inhibitor of NSUN2, thereby increasing sensitivity of the cancer cells to immunotherapy in the subject. Another aspect of the present invention provides a method of increasing efficacy of immunotherapy in treating cancer in a human subject receiving immunotherapy treatment, comprising administering (e.g., co-administering) to the subject receiving immunotherapy treatment an effective amount of an inhibitor of NSUN2. Attorney Docket No.9151.272.WO In some embodiments, the inhibitor of NSUN2 comprises a polypeptide comprising an amino acid sequence having at least about 70% sequence identity (e.g., at least about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% sequence identity or any value or range therein) to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33) or a compound, composition or combination comprising the same. In some embodiments, the inhibitor of NSUN2 comprises the amino acid sequence RRSR (SEQ ID NO:34). In some embodiments, the administering of an effective amount of the inhibitor of NSUN2 may inhibit NSUN2 activity in the cancer (e.g., inhibits NSUN2 activity in the cancer (e.g., in one or more cancer cells of the cancer) by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein), as compared to a control, for example, a cancer (e.g., one or more cancer cells of the cancer) in a human subject having the cancer and having not been administered the inhibitor of NSUN2. In some embodiments, the administering of an effective amount of the inhibitor of NSUN2 may reduce TREX2 expression and / or activity in the cancer (e.g., reduces TREX2 expression and / or activity in the cancer (e.g., in one or more cancer cells of the cancer) by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein), as compared to a control, for example, a cancer (e.g., one or more cancer cells of the cancer) in a human subject having the cancer and having not been administered the inhibitor of NSUN2. In some embodiments, the administering of an effective amount of the inhibitor of NSUN2 may enhance cGAS / STING expression and / or activity in the cancer (e.g., enhances cGAS / STING expression and / or activity in the cancer (e.g., in one or more cancer cells of the cancer) by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein), as compared to a control, for example, a cancer (e.g., one or more cancer cells of the cancer) in a human subject having the cancer and having not been administered the inhibitor of NSUN2. Cancers relevant to the invention include, but are not limited to, any cancer capable of developing resistance to immunotherapy. In some embodiments, the cancer may be, for Attorney Docket No.9151.272.WO example, breast cancer, prostate cancer, intestinal cancer (e.g., colon cancer), skin cancer (e.g., melanoma), liver cancer, and / or lung cancer, pancreatic cancer, head and neck cancer, brain cancer (e.g. glioblastoma), blood cancer (e.g. lymphoma), bladder cancer, and ovarian cancer In some embodiments, a method of the present invention may further comprise the step of administering to the subject one or more anti-cancer therapeutic agent and / or applying an anti-cancer treatment. Non-limiting examples of an anti-cancer therapeutic agent or treatment include immunomodulatory agents, anti-inflammatory agents, immunotherapy treatment (e.g., immunocheckpoint blockade agents), a surgical procedure, radiation, or any combination thereof. Additional non-limiting examples of an anti-cancer therapeutic agent or treatment include a cancer treatment selected from the group consisting of Doxorubicin, cyclophosphamide, 5-flurouracil, vinorelbine, pembrolizumab, nivolumab, durvalumab, Paclitaxel, Docetaxel, Oligomycin, JQ1, emodin, metformin, shikonin, physcion (6PGD inhibitor), AICAR, oxythiamine, leflunomide, lonidamine, polydatin, honokiol, dehydropiandrosterone (DHEA), venetoclax (ABT-199, Bcl-2 inhibitor), navitoclax (ABT- 263), A-1331852 (Bcl-xL inhibitor), ABT-737, S63845 (Mcl-1 inhibitor), immunotherapy treatment (e.g., anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-PD-1, anti-OX40, anti-GITR, anti- 4-1BB, or the like), any other chemotherapeutic agent, and any combination thereof. Additional nonlimiting examples of chemotherapeutic agents include daunomycin, cisplatin, oxaliplatin, carboplatin, verapamil, cytosine arabinoside, aminopterin, democolcine, tamoxifen, actinomycin D, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil mustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, and Temozolomide; Antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): Methotrexate, 5-fluorouracil (5-FU), Floxuridine, Cytarabine, 6- Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine, Natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins): Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Ara-C, paclitaxel (paclitaxel is commercially available as Taxol®), docetaxel, Mithramycin, Deoxyco- formycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN-a), Etoposide, and Teniposide; Other anti-proliferative cytotoxic agents are navelbene, CPT-11, anastrazole, Attorney Docket No.9151.272.WO letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine. Additional anti-proliferative cytotoxic agents include, but are not limited to, melphalan, hexamethyl melamine, thiotepa, cytarabine, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, topotecan, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons, interleukins, antiproliferative cytotoxic agents (including, but not limited to, EGFR inhibitors, Her-2 inhibitors, CDK inhibitors, and trastuzumab). In some embodiments, the therapeutic agent is a chemotherapeutic agent selected from the group consisting of epirubicin (EPI), doxorubicin, cisplatin, oxaliplatin, carboplatin, daunorubicin, taxol, docetaxel, gemcitabine, 5-fluorouracil, mitomycin, cytarabine, cytoxan, PARP inhibitors (e.g., Olaparib), anti-androgen therapy (e.g., enzalutamide, anti-estrogen agents, and any combination thereof. In some embodiments, the inhibitor of NSUN2 may be administered in a therapeutically effective amount. In some embodiments, for example, the inhibitor may be administered in a range of about 10 mg / Kg to about 100 mg / Kg, e.g., about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99 or 100 mg / Kg. In some embodiments, for example, the inhibitor may be administered once, twice, thrice, 4x, 5x, 6x, 7x, or more, per day, week, month, etc., for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more days, weeks, or months. For example, in some embodiments, the inhibitor may be administered in a range of about 10 mg / Kg to about100 mg / Kg, twice per week for 4 weeks. In some embodiments, the human subject may have previously received immunotherapy treatment. In some embodiments, the human subject may have not previously received immunotherapy treatment (e.g., may be naïve for immunotherapy treatment, e.g., an immunotherapy treatment naïve patient). In some embodiments, the cancer may have been, prior to the application of any one of the methods of the present invention, resistant to previously received immunotherapy treatment, e.g., at least about 5% resistant (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% resistant or any value or range therein) to previously received immunotherapy treatment. In some embodiments, the administering of the inhibitor of NSUN2 does not affect glucose metabolism in the subject, e.g., wherein normal glucose metabolism is substantially retained. In some embodiments, the administering of the inhibitor of NSUN2 minimally affects glucose metabolism, e.g., does not substantially effect glucose metabolism as compared to control, for example, glucose metabolism in a subject having or suspected of having cancer Attorney Docket No.9151.272.WO that is not administered the inhibitor of NSUN2 and / or, for example, glucose metabolism in a subject not having or suspected of having cancer (e.g., "normal" and / or "healthy" glucose metabolism). Immunotherapy treatment relevant to the invention includes any immunotherapy in clinical practice and / or those later developed. In some embodiments, the immunotherapy treatment may be immune checkpoint immunotherapy, also referred to as immune checkpoint inhibitors. Non-limiting examples of immunotherapy treatment include antagonist and / or agonist antibody therapy, such as anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-PD-1, anti- OX40, anti-GITR, anti-4-1BB, anti-CD47, anti-SIRP ^, or the like. The inhibitor of NSUN2 may be administered via any appropriate route, as would be within the knowledge of the skilled artisan, e.g., an oncologist, as needed for the conditions of the particular subject and / or patient. In some embodiments, the inhibitor may be administered topically (e.g., direct application), intravenously, cutaneously, subcutaneously, intraperitoneally, intra-arterially, intratumorally, intrathecally, intramuscularly, orally (e.g., by oral tablet or capsule), intranasally, sublingually, via inhalation, in an implant, in a matrix, in a gel, or any combination thereof. Also provided herein is a compound, composition or combination comprising a polypeptide comprising an amino acid sequence having at least 70% sequence identity (e.g., at least about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% sequence identity or any value or range therein) to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33). In some embodiments, the compound, composition or combination may comprise a polypeptide comprising an amino acid sequence RRSR (SEQ ID NO:34). Also provided herein is a non-naturally occurring polypeptide (e.g., an isolated, modified, synthetic, chimeric, recombinant and / or otherwise non-naturally polypeptide) comprising an amino acid sequence having at least 70% sequence identity (e.g., at least about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% sequence identity or any value or range therein) to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33). In some embodiments, the non-naturally occurring polypeptide (e.g., the isolated, modified, synthetic, chimeric, recombinant and / or otherwise non-naturally polypeptide) may comprise the amino acid sequence RRSR (SEQ ID NO:34). Attorney Docket No.9151.272.WO In some embodiments, a polypeptide or compound, composition, or combination comprising the same of the present invention may be for use in any one of the methods of the present invention. Polypeptides and fragments thereof of the invention can be modified for in vivo use by the addition, at the amino- and / or carboxyl-terminal ends, of a blocking agent to facilitate survival of the relevant polypeptide in vivo. This can be useful in those situations in which the polypeptide termini tend to be degraded by proteases prior to cellular uptake. Such blocking agents can include, without limitation, additional related or unrelated peptide sequences that can be attached to the amino and / or carboxyl terminal residues of the polypeptide to be administered. This can be done either chemically during the synthesis of the polypeptide or by recombinant DNA technology by any suitable methods. For example, one or more non-naturally occurring amino acids, such as D- alanine, can be added to the termini. Alternatively, blocking agents such as pyroglutamic acid or other molecules known in the art can be attached to the amino and / or carboxyl terminal residues, or the amino group at the amino terminus or carboxyl group at the carboxyl terminus can be replaced with a different moiety. Additionally, the polypeptide terminus can be modified, e.g., by acetylation of the N-terminus and / or amidation of the C-terminus. Likewise, the peptides can be covalently or noncovalently coupled to pharmaceutically acceptable "carrier" proteins prior to administration. These and other modifications to polypeptides contemplated to provide protease resistance, including but not limited to, backbone extension, side chain substitution, cyclization of the polypeptide, and / or conjugation to the N- and / or C-terminus and / or polypeptide side chain are further described in Lucana et al.2021 Pharmaceutics 13:2065, incorporated herein by reference in its entirety. Polypeptides and fragments thereof of the invention can also be modified to comprise (e.g., linked, conjugated, bound (e.g., covalently bound, non-covalently bound), complexed, encapsulated, etc.) to and / or with one or more detectable moiety. Any suitable detectable moiety known in the art can be used in the practice of the present invention, and the detectable moiety can be detected using any method known in the art. For example, in some embodiments, the detectable moiety may be an exogenous epitope or chemical label that is attached to the polypeptide. Non-limiting examples of detectable moieties include an epitope, an enzyme, a ligand, a receptor, an antibody or antibody fragment and the like. In some embodiments, a detectable moiety of the invention may be a fluorescent moiety (e.g., GFP, EFP, RFP and the like), a peptide tag (e.g., FLAG, e.g., FLAG-tag), an antibody or fragment thereof, hemagglutinin antigen, polyHis, biotin, Protein A, streptavidin, maltose binding protein, c- Attorney Docket No.9151.272.WO myc, an enzyme such as glutathione-S-transferase, alkaline phosphatase, horseradish peroxidase, β-glucuronidase, β-galactosidase or luciferase, a radioactive moiety and / or an electron-dense moiety such as a ferritin or gold particle(s). The detectable moiety can be detected either directly or indirectly using any suitable method. For example, for direct detection, the tag or reagent can comprise a radioisotope (e.g.,35S) and the presence of the radioisotope detected by autoradiography. As another example, the tag or reagent can comprise a fluorescent moiety and be detected by fluorescence as is known in the art. Alternatively, the tag or reagent comprising the detectable moiety can be indirectly detected, i.e., the detectable moiety requires additional reagents to render it detectable. Illustrative methods of indirect labeling include those utilizing chemiluminescence agents, chromogenic agents, enzymes that produce visible reaction products, and ligands (e.g., haptens, antibodies or antigens) that may be detected by binding to labeled specific binding partners (e.g., hapten binding to a labeled antibody or a first antibody binding to a second antibody). In some embodiments, the detectable moiety may be an antibody or antibody fragment. A variety of protocols for detecting the presence of and / or measuring the amount of antibodies or other polypeptides are known in the art. Examples of such protocols include, but are not limited to, enzyme-linked immunosorbent assays (ELISA), radioimmunoassays (RIA), radioreceptor assay (RRA), competitive binding assays and immunofluorescence microscopy. These and other assays are described, among other places, in Hampton et al. (Serological Methods, a Laboratory Manual, APS Press, St Paul, Minn (1990)) and Maddox et al. (J. Exp. Med.158:1211-1216 (1993)). In some embodiments, a polypeptide, compound, composition or combination of the present invention may further comprise a pharmaceutically acceptable carrier (e.g., a pharmaceutical formulation). By "pharmaceutically acceptable" it is meant a material that is not toxic or otherwise undesirable, i.e., the material may be administered to a subject without causing any undesirable biological effects. In some embodiments, the present invention provides a pharmaceutical composition comprising a polypeptide, compound, composition or combination of the present invention in a pharmaceutically acceptable carrier and, optionally, other medicinal agents, pharmaceutical agents, stabilizing agents, buffers, carriers, adjuvants, diluents, etc. For injection, the carrier will typically be a liquid. For other methods of administration, the carrier may be either solid or liquid. For inhalation administration, the carrier will be respirable, and will preferably be in solid or liquid particulate form. Attorney Docket No.9151.272.WO Another aspect of the present invention relates to a kit comprising the polypeptide, compound, composition or combination of the present invention and useful for carrying out the methods of the invention. The kit may further comprise additional reagents for carry out the methods (e.g., buffers, containers, additional therapeutic agents) as well as instructions for use. Another aspect of the present invention provides for use of a polypeptide, compound, composition or combination of the present invention in reducing resistance to immunotherapy in a cancer cell, reducing oncogenic activity of a cancer cell, reducing Warburg effect in a cancer cell, inhibiting binding of glucose and NSUN2 in a cell, inhibiting NSUN2 activity in a cell, treating cancer, increasing sensitivity of a cancer cell to immunotherapy, and / or increasing efficacy of immunotherapy in treating cancer. Another aspect of the invention provides for preparation of a medicament for use comprising the polypeptide, compound, composition or combination of the present invention. The invention will now be described with reference to the following examples. It should be appreciated that these examples are not intended to limit the scope of the claims to the invention but are rather intended to be exemplary of certain embodiments. Any variations in the exemplified methods that occur to the skilled artisan are intended to fall within the scope of the invention. EXAMPLES Example 1: NSUN2 as a novel interacting protein of Glucose. To identify the direct sensors of glucose, biotin-labeled glucose was synthesized, incubated with cell lysate from HEK293 cells and potential glucose interacting proteins pulled down by Streptavidin beads, followed by systematic mass spectrometry analysis (FIG. 1 panel A). Several proteins that potentially interact with biotin-glucose, but not biotin, were identified from mass spectrometry analysis (Table 1). NSUN2 was selected for further characterization and study, as NSUN2, an RNA 5-methylcytosine (m5C) methyltransferase that triggers m5C RNA methylation including mRNA and tRNA to orchestrate RNA stability, was identified as an oncoprotein via its promotion of m5C RNA methylation of diverse targets such as HGDF (Chellamuthu and Gray, 2020; Chen et al., 2019; Hu et al., 2021; Mei et al., 2020) and is overexpressed in numerous human cancers (Chellamuthu and Gray, 2020). In this study, interaction of NSUN2 with glucose was verified through biotin and biotin-glucose incubated with cell lysates from diverse cell lines, and such interaction was disrupted by adding unlabeled glucose (FIG.1 panels B and C; FIG.8 panel A). As a positive Attorney Docket No.9151.272.WO control for the assay, it was demonstrated that biotin-glucose could bind to DDX21 (Miao et al., 2023), and such interaction can be abrogated by unlabeled glucose, indicating that this approach can be used to identify potential glucose binding proteins (FIG. 8 panels B-C). In vitro binding assays using recombinant NSUN2 proteins were performed to assess the direct interaction between glucose and NSUN2. FIGS. 1D and 1E revealed that biotin-glucose directly interacts with NSUN2, which has three isoforms, including NSUN2-F1 (amino acid (aa) 1-767), NSUN2-F2 (aa 85-120: (SEQ ID NO:35) SHAKEILHCLKNKYFKELEDLEVDGQKVEVPQPLSW→ R), and NSUN2-F3 (Δ aa 1- 236) (FIG.8 panels D-F) (Ota et al., 2004). Notably, the results from this study showed that glucose directly interacts with NSUN2-F1 and NSUN2-F2, but not NSUN2-F3 (FIG.1 panels D and E), indicating that NSUN2 aa 1-236, but not aa 85-120 and aa 237-767, is required for glucose binding. Various NSUN2 truncated mutants were generated from the N-terminal region of NSUN2 (aa 1-236) and subjected to in vitro glucose binding assays (FIG. 8 panel G). The NSUN2 mutant with aa 1-84 deletion, but not other mutants, failed to interact with glucose, indicating the requirement of aa 1-84 of NSUN2 for glucose binding (FIG.1 panels F and G). Three further mutants of NSUN2 were generated from aa 1-84 (FIG.8 panels H and I). Using these mutants, it was found that NSUN2 mutant with deletion of aa 1-28, but not other mutants, no longer interacted with glucose (FIG.1 panels H and I), suggesting that aa 1-28 of NSUN2 may be a region for glucose binding. To validate this notion, a cell-penetrating TAT-n28 peptide and a control TA peptide was generated by fusing aa 1-28 from NSUN2 or a control peptide randomly swapped from NSUN2 aa 1-28 with a trans-activator of transcription (TAT) tag placed in the N-terminal region (FIG.1 panel J), which allows for the peptide to get into cells (Milletti, 2012; Zhang et al., 2019). Results showed that TAT-N28 peptide, but not control TAT peptide, could directly interact with glucose (FIG. 1 panel K). Remarkably, TAT-N28 peptide disrupted in vitro glucose / NSUN2 binding in a dose-dependent manner (FIG.1panel L). Collectively, these data show that glucose directly binds to NSUN2 at aa 1-28 and the TAT- N28 peptide could abolish glucose / NSUN2 binding. By blasting NSUN2 N28 peptide against 40 other potential glucose interacting proteins identified from mass spectrometry analysis (Table 1), it was found that the motif (RRSR; SEQ ID NO:34) observed in the NSUN2 N28 peptide also appears in some of these proteins including SRSF8, U2AF2, SRSF10, and LUC7L (Table 2). This may suggest that glucose can also bind to these proteins via the motif (RRSR; SEQ ID NO:34). Attorney Docket No.9151.272.WO Glucose serves as a cofactor to directly promote oligomerization and activation of NSUN2: Global m5C RNA methylation is mediated by DNA methyltransferase 2 (DNMT2) and NOP2 / SUN RNA methyltransferase family members (NSUN) (Cheng et al., 2018; Gkatza et al., 2019; Xie et al., 2020; Xue et al., 2020). Data in this study demonstrates that NSUN2 is a primary enzyme mediating global m5C RNA methylation in various cancer cell lines, such as Hep3B (liver cancer) and PC3 (prostate cancer), as NSUN2 knockdown impaired global m5C RNA methylation in a Dot blot assay (FIG.9 panels A-D). Since glucose directly interacts with NSUN2, it was next asked whether glucose could impact NSUN2 m5C RNA methyltransferase activity by monitoring the levels of m5C RNA methylation in these cell lines. It was found that deprivation in these cancer cell lines markedly impaired m5C methylation levels indicative of defective NSUN2 activity, while add-back of glucose at physiological levels (5.5 mM) rescued the defect in m5C RNA methylation levels (FIG.2 panels A-C; FIG. 9 panel E). The rescued effect on m5C RNA methylation levels by glucose was shown to depend on the presence of NSUN2 (FIG.2 panel D; FIG.9 panel F). Add-back of 5.5 mM 2-Deoxy-D-glucose (2DG), a glucose derivative that cannot be metabolized by HK and serves as a HK / glycolysis inhibitor (Pajak et al., 2019), also rescued the defect in m5C RNA methylation levels (FIG.2 panel E; FIG.9 panel G). Similar to biotin- glucose, biotin-2DG could also bind to NSUN2, and such interaction was disrupted by the unlabeled 2DG (FIG. 2 panels F-H). This suggested that glucose metabolism may be dispensable for the effect of glucose on regulating NSUN2 activity. In support of this notion, studies were conducted to block glucose metabolism toward glycolysis by HK2 knockdown. HK2 is a key isoform of HK frequently overexpressed in cancer cells (Hay, 2016), but knocking down HK2 failed to block the effect of glucose on rescuing m5C RNA methylation levels. Instead, HK2 loss appeared to enhance the effect of glucose on rescuing m5C RNA methylation (FIG. 2 panel I; FIG. 9 panels H-J), presumably due to glucose accumulation caused by the failure in glucose metabolism upon HK2 loss. Moreover, NSUN2 overexpression cooperated with glucose to promote m5C RNA methylation levels (FIG.2 panel J; FIG. 9 panels K-M). These data support the results described above in disrupting glucose / NSUN2 binding by TAT-N28 peptide, which impaired m5C RNA methylation levels in a dose dependent manner (FIG. 1 panel L; FIG.2 panel K; FIG.9 panel N). Collectively, these results show that glucose maintains global m5C RNA methylation and NSUN2 activity in vivo through glucose / NSUN2 binding independently of its metabolism. To assess whether glucose could directly promote NSUN2 methyltransferase activity, Attorney Docket No.9151.272.WO in vitro m5C RNA methylation assays were performed using recombinant NSUN2 proteins along with glucose. Glucose exhibited a dose-dependent effect to directly promote in vitro NSUN2 methyltransferase (FIG.2 panel L). Glucose at physiological levels enhanced NSUN2 methyltransferase activity for more than 3 fold compared with vehicle control (FIG.2 panels L and 2M). Consistently, the glucose derivative 2DG also promoted NSUN2 methyltransferase activity in vitro, similar to glucose (FIG. 2 panel M). However, downstream metabolite products of glucose, including glucose-6-phosphate (G6P), fructose 1,6-biphosphate (FBP), fructose 6-phosphate (F6P), myo-inositol (Ins) and pyruvate (Pyr) displayed either no effect or only modest effect on promoting NSUN2 methyltransferase (FIG. 2 panel M). These data further support that glucose directly promotes NSUN2 methyltransferase activity in vitro independently of its metabolism. In further support thereof, data showed that glucose failed to enhance the activity of NSUN2 mutant (Δ aa 1-28) defective in glucose binding, while it promoted the activity of other NSUN2 deletion mutants that retained glucose binding function in vitro (FIG.1 panel I; FIG.2 panel N). In addition, disrupting glucose / NSUN2 binding by the TAT-N28 peptide impaired the effect of glucose on promoting NSUN2 activity both in vitro and in vivo (FIG.1 panel L; FIG.2 panels K and O; FIG.9 panel N). Collectively, these data show that glucose serves as a cofactor that directly binds to NSUN2 at aa 1-28 to promote NSUN2 methyltransferase activity. Protein dimerization and / or oligomerization processes have been shown to play an important role in activation of diverse enzymes including HK (Srivastava et al., 2020; Xie and Wilson, 1990) and PKM2 (Hitosugi et al, 2009; Wang et al., 2014). To determine whether glucose may impact the dimerization and / or oligomerization levels of NSUN2, dimerization and oligomerization of recombinant NSUN2 proteins in the presence or absence of glucose was monitored using two independent methods, including native gel and chemical crosslinking approaches. NSUN2 oligomerization examined by native gel was markedly enhanced by glucose in a dose-dependent manner (FIG. 2 panel P). The monomer of NSUN2 was not detected under this native gel approach, but glucose did not increase total NSUN2 protein levels under the SDS denatured condition, which detects all forms of NSUN2 (FIG. 2 panel P). To validate this notion further, chemical cross-linking assays were conducted, whereby it was found that glucose induced NSUN2 oligomerization but reduced NSUN2 monomer and dimer in a dose-dependent manner (FIG.2 panels R and S). Notably, glucose failed to promote the oligomerization of NSUN2 mutant (Δ aa 1-28) defective in glucose binding (FIG.2 panels V and W), consistent with the defect in promoting NSUN2 activity by glucose (FIG.2 panel Attorney Docket No.9151.272.WO N). Disrupting glucose / NSUN2 binding by the TAT-N28 peptide abrogated glucose-mediated NSUN2 oligomerization (FIG.2 panels X and Y), consistent with the impairment of glucose effect on promoting NSUN2 activity (FIG.2 panels K and 2O; FIG.9 panel N). Collectively, these data show that glucose / NSUN2 binding promotes NSUN2 oligomerization and activity. Glucose / NSUN2 binding leading to NSUN2 activation maintains oncogenic activity of cancer cells: Glucose maintains cancer cell proliferation, survival and cancer stemness critical for cancer development. Consistently, glucose deprivation leading to defective NSUN2 activity impaired cancer stemness of Hep3B and PC3 cancer cells as determined by cancer sphere assay, and add-back of glucose rescued this defect (FIG.3 panel A; FIG.10 panel A). To assess whether glucose metabolism is sufficient for mediating oncogenic processes of glucose, viability and sphere assays were performed in cancer cells under glucose deprivation and added back G6P (by transfection) (Guo et al., 2022) with or without non-metabolizable glucose analog, 2DG or 3-O-methyl-D-glucose (3OMG) (Miao et al., 2023). Add-back of G6P, 2 DG or 3OMG alone, was found not sufficient for rescuing the defect in cancer sphere and colony formation (FIG.3 panels B and C; FIG.10 panels B and C). However, the combination of G6P with either 2DG or 3OMG fully rescued these defects (FIG. 3 panel C; FIG. 10 panel C). Collectively, these data indicate that glucose metabolism is not sufficient for glucose-mediated oncogenic processes, and direct glucose action is necessary for maintaining these biological processes. Similar to glucose deprivation, NSUN2 knockdown also impaired cancer cell survival, proliferation and cancer stemness, correlated with reduced expression of cancer stem cell factors Oct4 and Sox2 (FIG. 3 panels D-3G; FIG. 10 panels D-G). Loss of NSUN2 compromised the tumorigenicity of Hep3B and PC3 cells in an in vivo xenograft tumorigenesis assay (FIG.3 panel H; FIG.10 panel H), indicative of the oncogenic role of NSUN2 in these cancer cell lines. Further experiments were performed to assess whether glucose / NSUN2 binding for NSUN2 serves as a mechanism to maintain oncogenic processes. Glucose / NSUN2 binding disrupted by the TAT-N28 peptide led to impaired NSUN2 activity and impaired cancer cell proliferation, survival and cancer stemness (FIG.3 panels I-K; FIG.10 panels J-K). However, these effects did not appear to result from affecting ATP levels, as TAT-N28 peptide failed to block glucose-mediated ATP production (FIG. 10 panel L). Restoration of NSUN2, but not NSUN2 mutant ( ^ aa 1-28), rescued the defect in these oncogenic properties in NSUN2 knockdown cancer cells, correlated with expression of OCT4 and SOX2 (FIG.3 panels L-R). Attorney Docket No.9151.272.WO Furthermore, glucose restoration rescued cancer cell survival upon glucose deprivation, but loss of NSUN2 or impaired glucose / NSUN2 binding abrogated the rescue effect of glucose (FIG. 3 panel Q). In a xenograft tumorigenesis assay, NSUN2, but not NSUN2 mutant ( ^ aa 1-28), rescued the defect in tumorigenicity upon NSUN2 knockdown (FIG. 3 panel R). Collectively, these data suggest that glucose / NSUN2 binding driving NSUN2 activation maintains oncogenic activity of cancer cells. Glucose / NSUN2 Axis Maintains TREX2 Expression to Execute Its Oncogenic Activity: NSUN2 methyltransferase triggers m5C RNA methylation and stability of its RNA targets. In the bladder cancer cell model, NSUN2 triggers m5C RNA methylation and stability of HDGF mRNA, leading to the promotion of bladder cancer development (Chen et al., 2019). In this study, systematic RNA sequencing (RNA-seq) was conducted along with RNA immunoprecipitation (RNA-IP) to dissect the m5C RNA methylation targets of glucose / NSUN2 responsible for its oncogenic activity. RNA-seq revealed that 122 genes were induced by glucose in a NSUN2-dependent manner (FIG.4 panel A; Table 3). RNA-seq results for some of these targets, such as TREX2, HNF4A, SREBF1, HES2, and NEUROD2, were further confirmed by real time qPCR (FIG.4 panel B; FIG.11 panel A). Immunoblotting assay further demonstrated that the protein expression of these targets was induced by glucose / NSUN2 axis (FIG. 4 panels C-G; FIG. 11 panels B-G). Glucose induced TREX2 mRNA expression in control and NSUN2 knockdown cells restored with NSUN2, but not in NSUN2 knockdown cells restored with NSUN2 mutant ( ^ aa 1-28) (FIG. 4 panel H). Collectively, these data indicate that glucose links to NSUN2 activation to maintain RNA and protein expression in a subset of its targets. Using RNA-IP to assess the m5C RNA methylation in these affected genes by glucose / NSUN2 axis, it was found that only TREX2, but not other targets, consistently underwent m5C RNA methylation in a manner dependent on both glucose and NSUN2 (FIG. 4 panel I; FIG.11 panel H). Glucose induced m5C RNA levels of TREX2 in control and NSUN2 knockdown cells restored with NSUN2, but not in NSUN2 knockdown cells restored with NSUN2 mutant ( ^ aa 1-28) (FIG.4 panels I, J). Notably, blocking glucose / NSUN2 binding by the TAT-N28 peptide impaired glucose-induced m5C RNA levels of TREX2 (FIG.4 panel J). Collectively, these data indicate that glucose / NSUN2 binding appears is needed for inducing m5C RNA methylation of TREX2. TREX2 exhibits an exonuclease activity that degrades single strand DNA (ssDNA) and double strand DNA (dsDNA) similar to its closely related protein, TREX1 (Hemphill and Attorney Docket No.9151.272.WO Perrino, 2019; Mazur and Perrino, 2001). Notably, TREX1 is a key repressor for the cGAS / STING pathway involved in cancer and immune regulation (Ablasser et al., 2014; Gao et al., 2015; Hemphill et al., 2021; Vanpouille-Box et al., 2017). TREX2 gene was selected among these targets to further characterize its involvement in glucose / NSUN2-mediated oncogenic processes. The mRNA and protein expression of TREX2 was induced by glucose in various cancer cells in a NSUN2-dependent manner, and NSUN2 overexpression promoted mRNA and protein expression of TREX2 (FIG. 4 panels A-H; FIG. 11 panels E-G; FIG. 11 panel I). Induction of mRNA and m5C RNA methylation levels of TREX2 by glucose strictly depends on NSUN2 and glucose / NSUN2 binding (FIG. 4 panels G-I; FIG. 11 panels J-M). Notably, restoration of NSUN2, but not of NSUN2 mutant ( ^ aa 1-28), rescued the defect in mRNA and protein expression and m5C RNA methylation levels of TREX2 in NSUN2 knockdown cells (FIG.4 panels G-I). Moreover, disrupting glucose-NSUN2 interaction by the TAT-N28 peptide impaired TREX2 m5C RNA methylation and protein induction by glucose (FIG. 4 panels J and K). In line with the results for m5C RNA methylation of TREX2, both glucose deprivation and NSUN2 loss markedly reduced TREX2 mRNA stability, but not mRNA stability of ACTIN and NSUN2 (FIG.4 panel L; FIG.11 panel N), which was rescued by glucose or NSUN2 restoration, but not by NSUN2 mutant ( ^ aa 1-28). Conversely, NSUN2 overexpression promoted TREX2, but not ACTIN and NSUN2, mRNA stability (FIG.4 panel M; FIG. 11 panel O). RNA-IP assay revealed that the region (aa 85-120) within N-terminal domain (NTD) of NSUN2 is required for NSUN2 binding to TREX2 mRNA (FIG.4 panels N and O; FIG. 11 panel P), consistent with the earlier study showing that NSUN2 binds to its target mRNA through its NTD (Sibbritt et al., 2013). Glucose / NSUN2 axis promoted TREX2 mRNA and protein expression, but not TREX1 mRNA and protein expression (FIG.12 panels A-H). Collectively, these data indicate that glucose acts through NSUN2 binding to maintain m5C RNA methylation and mRNA stability of TREX2. It was then determined whether TREX2 displays oncogenic activity and is responsible for oncogenic activity of glucose / NSUN2 axis. TREX2 knockdown impaired cancer cell proliferation, survival, cancer stemness (FIG.12 panels I-M), whereas TREX2 overexpression promoted these oncogenic properties (FIG. 4 panels P-T; FIG. 11 panel Q). While glucose restoration protected cancer cells from cell death upon glucose deprivation, loss of NSUN2 or TREX2 abrogated protection effect of glucose (FIG. 4 panel S; FIG. 12 panel M). Notably, restoration of TREX2 rescued not only cell death from glucose deprivation or NSUN2 loss (FIG.4 panel S) but also the defects in cancer cell proliferation, survival, and cancer stemness Attorney Docket No.9151.272.WO upon NSUN2 knockdown (FIG. 4 panels Q-S; FIG. 11 panel Q). In a xenograft assay, overexpression of TREX2 promoted tumorigenesis, and restoration of TREX2 rescued the defect in tumorigenicity potential upon NSUN2 loss (FIG.4 panel T). Collectively, these data underscore the importance of TREX2 in mediating oncogenic activity of glucose / NSUN2 axis. Glucose / NSUN2 / TREX2 Axis Restricts Cytosolic dsDNA Accumulation for cGAS / STING Activation to Maintain Oncogenic Activity of Cancer Cells: Although TREX2 is closely related to TREX1, which is involved in cGAS / STING repression by removing cytosolic ssDNA and dsDNA, the functional role of TREX2 in cGAS / STING signaling and cancer regulation remain unclear. Accumulating evidence revealed that cGAS / STING pathway not only activates innate immunity for T cell activation, but also serves as a tumor suppressive signal by inducing apoptosis and cellular senescence in a cell autonomous manner (Li and Chen, 2018). Since TREX2 serves a key player responsible for oncogenic activity of glucose / NSUN2 axis, it was next determined whether TREX2 impacts cGAS / STING activation to maintain oncogenic activity of glucose / NSUN2 / TREX2 axis. Similar to TREX1 deficiency (Ablasser et al., 2014; Gao et al., 2015; Hemphill et al., 2021; Vanpouille-Box et al., 2017), loss of TREX2 also triggered spontaneous activation of cGAS / STING pathway, as determined by elevated 2′3′-cGAMP (cGAMP) for cGAS activation, phospho-STING (p- STING), phospho-TBK1 (p-TBK1), phospho-IRF3 (p-IRF3), type I interferon- ^ (IFN-β) production and IFN response gene (LGALS9) expression (Shaw et al., 2017) without changes in cGAS protein level, accompanied by elevated caspase-3 activation indicative of apoptosis (FIG. 13 panels A-E). Like TREX2 loss, glucose deprivation and NSUN2 loss also elevated cGAMP, p-STING, p-TBK1, p-IRF3, IFN-β production, IFN response gene (LGALS9) expression and caspase-3 activation without changes in cGAS protein level (FIG.5 panels A and B; FIG. 13 panels F-W), which could be reversed by glucose and NSUN2, respectively, but not NSUN2 mutant ( ^ aa 1-28) (FIG. 5 panels B and C). Loss of NSUN2 impaired the suppressive effect of glucose on p-STING, p-TBK1, p-IRF3, IFN-β production and caspase-3 activation (FIG.5 panels A and 5B; FIG.13 panels U and V). Notably, adding 2DG and 3OMG, but not G6P, rescued TREX2 expression and repressed cGAS / STING and caspase-3 activation in cell-based assays under glucose starvation (FIG. 13 panels J-L). Furthermore, blocking glucose / NSUN2 interaction by the TAT-N28 peptide also enhanced the levels of p-STING, p-TBK1, p-IRF3, IFN-β production and caspase- 3 activation and compromised the suppressive effects of glucose (FIG. 5 panels D and E), accompanied by reduced TREX2 protein level (FIG. 4 panel K). Furthermore, elevated Attorney Docket No.9151.272.WO cGAMP, p-STING, p-TBK1, p-IRF3, IFN-β production and caspase-3 activation upon NSUN2 loss could be rescued by TREX2 restoration (FIG.5 panels F and G; FIG.13 panel X). While glucose, NSUN2 or TREX2 overexpression suppressed the levels of p-STING, p-TBK1 and p- IRF3, IFN-β production and caspase-3 activation (FIG.14 panels A-D), the suppressive effects of glucose could be reversed by TREX2 knockdown or by adding cGAMP (FIG.5 panels H and I; FIG.14 panel E). Notably, elevated p-STING, p-TBK1 and p-IRF3, IFN-β production and caspase-3 activation upon glucose deprivation or NSUN2 loss could be reversed upon loss of STING or cGAS (FIG.5 panels J and K; FIG. 14 panels F-J). Previous study showed that AMPK can regulate innate immunity through directly phosphorylating TBK1 (Zhang et al., 2022). In this study, the involvement of AMPK in cGAS / STING activation upon glucose deprivation was ruled out, as AMPK inactivation by its inhibitor compound C or AMPK deficiency failed to compromise cGAS / STING activation induced by glucose deprivation (FIG. 14 panels K and L). Collectively, these data indicate that the glucose / NSUN2 / TREX2 axis serves as a key repressor to restrict cGAS / STING activation. Cytosolic dsDNA accumulation is known to drive activation of cGAS / STING pathway (Chen et al., 2016). In this study, analyses were performed indicating that glucose deprivation triggered spontaneous cytosolic dsDNA accumulation, which was reversed by glucose add- back (FIG.5 panel L; FIG.15 panels A-D). The accumulation of cytosolic DNA included both cytosolic ssDNA and dsDNA upon glucose deprivation (FIG. 15 panels A-D). Similar to glucose deprivation, loss of NSUN2 or TREX2 also induced cytosolic dsDNA accumulation (FIG. 5 panels L and M; FIG. 15 panels E-J). TREX2 was found to be localized both in the nucleus and cytosol (FIG.16 panels A and B). Notably, restoration of NSUN2, but not NSUN2 mutant ( ^ aa 1-28), rescued cytosolic dsDNA accumulation in NSUN2 knockdown cancer cells (FIG. 15 panels F and G). While add-back of glucose rescued spontaneous cytosolic dsDNA accumulation upon glucose deprivation, this effect was abolished by the TAT-N28 peptide, NSUN2 knockdown or TREX2 knockdown (FIG.5 panels L-O; FIG.15 panels I and J; FIG. 16 panels C-F). Moreover, add-back of TREX2 abrogated spontaneous cytosolic dsDNA accumulation upon glucose deprivation or NSUN2 knockdown (FIG. 16 panels G-J). Collectively, these data indicate that glucose / NSUN2 / TREX2 axis serves as a key mechanism to restrict cytosolic dsDNA accumulation. TREX1 displays 3’ to 5’ exonuclease activity to remove cytosolic dsDNA (Grieves et al., 2015). To investigate whether there is a redundant role of TREX1 and TREX2 in regulating cytosolic dsDNA levels, TREX1 knockdown, TREX2 knockdown and TREX1 / TREX2 double Attorney Docket No.9151.272.WO knockdown cells were generated. TREX1 knockdown consistently caused the accumulation of cytosolic dsDNA, similar to TREX2 knockdown. However, both TREX1 and TREX2 knockdown did not further enhance cytosolic dsDNA levels compared with TREX1 knockdown or TREX2 knockdown (FIG. 15 panels G and H), suggesting that TREX1 and TREX2 play a non-redundant role in regulating cytosolic dsDNA levels. These data suggest that TREX1 and TREX2 may work together to reduce cytosolic dsDNA levels, in line with a recent review which indicated that TREX1 and TREX2 are functional dimers (Hemphill and Perrino, 2019). TREX2 was shown to be associated with DNA repair processes in mouse ES cells (Dumitrache et al., 2009). To understand if spontaneous DNA damage occurs upon TREX2 knockdown, ^H2AX levels were examined using immunoblotting assay. ^H2AX was only slightly induced upon TREX2 knockdown compared with control knockdown cancer cells, indicating that DNA damage response may not be induced by TREX2. While the low basal of ^H2AX detected under glucose deprivation is inhibited by glucose, loss of TREX2 abrogated this suppression effect by glucose (FIG.17 panel C). Since cGAS / STING serves as a tumor suppressor signal by inducing apoptosis, it was next determined whether the oncogenic activity induced by glucose / NSUN2 / TREX2 axis may act through cGAS / STING repression. As expected, cGAS or STING knockdown reduced basal levels of p-STING, p-TBK1 and p-IRF3 and caspase-3 activation and promoted cancer cell proliferation, survival and cancer stemness (FIG. 14 panels F and G; FIG. 17 panels D-I). Remarkably, cGAS or STING knockdown rescued the defects in cancer cell proliferation, survival and cancer stemness upon NSUN2 knockdown (FIG.5 panels P-S). Moreover, cGAS or STING knockdown also rescued the defect in cell survival upon glucose deprivation (FIG. 5 panel S). In a xenograft assay, cGAS knockdown or STING knockdown also rescued the defect in tumorigenesis upon NSUN2 loss (FIG. 5 panel T). Collectively, these data indicate that the glucose / NSUN2 / TREX2 axis maintains oncogenic properties by restricting cGAS / STING activation. Glucose / NSUN2 / TREX2 Axis Drives Anti-PD-L1 Immunotherapy Resistance through Restricting cGAS / STING Signaling: cGAS / STING signaling activation plays a critical role in maintaining the efficacy of anti-PD-1 / anti-PD-L1 immunotherapy in cancer suppression (Ablasser and Chen, 2019; Du et al., 2021; Fu et al., 2015; Wang et al., 2017). As glucose / NSUN2 / TREX2 axis restricts cGAS / STING activation, it was hypothesized that aberrant activation of glucose / NSUN2 / TREX2 may drive the resistance of cancer cells to anti- Attorney Docket No.9151.272.WO PD-L1 immunotherapy. To address this question, overexpression experiments were performed with vector, NSUN2 or NSUN2 mutant ( ^ aa 1-28) in B16 melanoma cells and CT26 colon cancer cells, both of which are sensitive to anti-PD-L1 immunotherapy (Curran et al., 2010; Pilon-Thomas et al., 2010; Sagiv-Barfi et al., 2015). NSUN2, but not NSUN2 mutant ( ^ aa 1- 28), induced TREX2 expression and led to cGAS / STING signaling suppression (FIGS. S11A and S11B). In B16 syngeneic tumor model with intact immunity, NSUN2, but not NSUN2 mutant ( ^ aa 1-28), promoted tumorigenesis and caused the resistance of B16 tumor to anti- PD-L1 immunotherapy (FIG.6 panels A and B). Similar results were also obtained in CT26 tumor model (FIG. 6 panels C and D). Of note, loss of TREX2 abolished tumor promotion effect and resistance to anti-PD-L1 immunotherapy induced by NSUN2 overexpression (FIG. 6 panels E and F; FIG.18 panels C-F). In the tumor sections, overexpression of NSUN2, but not NSUN2 mutant ( ^ aa 1-28), reduced cGAS / STING signaling, as determined by reduced p- STING, p-TBK1 and p-IRF3 levels, caspase-3 activation indicative of apoptosis, CD3+and CD8+T cell infiltration upon anti-PD-L1 immunotherapy treatment (FIG.6 panels G-L, FIG. 18 panel G). Collectively, these data indicate that the glucose / NSUN2 / TREX2 axis drives cGAS / STING signaling repression and anti-PD-L1 immunotherapy resistance by restricting apoptosis and CD8+T cell infiltration. To understand whether genetically targeting glucose / NSUN2 / TREX2 axis is a promising strategy to overcome anti-PD-L1 immunotherapy resistance in those cold tumors, knockdown experiments of NSUN2 or TREX2 were performed in 4T1 breast cancer cells and TRAMP-C2 prostate cancer cells, which are unresponsive to anti-PD-L1 immunotherapy (Chen et al., 2022; Oba et al., 2020). NSUN2 loss and TREX2 loss in these two cancer cell lines also induced cGAS / STING signaling activation (FIG.19 panels A-D). Further, NSUN2 or TREX2 loss could reduce tumorigenesis and overcome anti-PD-L1 immunotherapy resistance in these syngeneic tumor models (FIG. 7 panels A-D). However, STING loss restored the tumorigenesis and abolished the reversal effect of anti-PD-L1 immunotherapy resistance upon NSUN2 or TREX2 deficiency (FIG.7 panels A-D; FIG.19 panels E-J). In the tumor sections, NSUN2 or TREX2 loss induced cGAS / STING signaling, caspase-3 activation, and CD3+and CD8+T cell infiltration in response to anti-PD-L1 immunotherapy, which were impaired upon STING loss (FIG.7 panels E-G; FIG.19 panels K-N). Collectively, these data indicate that targeting glucose / NSUN2 / TREX2 axis could suppress tumorigenesis and overcome anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS / STING activation for apoptosis and CD8+T cell infiltration. Attorney Docket No.9151.272.WO In summary, this study identified NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS / STING inactivation. It was found that glucose serves as a signaling molecule that directly binds to and activates NSUN2 to maintain m5C RNA methylation and mRNA stability of TREX2, resulting in cGAS / STING repression, the shut off interferon responses and promotion of oncogenic processes and immunotherapy resistance (FIG.7 panel H), These studies also indicate that targeting the glucose / NSUN2 / TREX2 axis provides a strategy to elicit cGAS / STING activation leading to enhanced tumor cell apoptosis and CD8+T cell infiltration, for cancer targeting, and for overcoming immunotherapy resistance in cold tumors such as prostate cancer that are refractory to immunotherapy. Example 2: Methods as used in Example 1. The synthesis of biotin-glucose: A suspension of 180 mg of glucose (1 mM), 384 mg of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (2 mM) and 11 mg of 4-dimethylaminopyridine (DMAP) (0.01 mM) in dichloromethane (DCM) (5 mL) was stirred at room temperature (RT).244 mg of biotin (1 mM) in 5 mL of DCM was added and the reaction mixture was stirred continually overnight. The solvent was removed, and the final compound were purified by silica gel column chromatography using a gradient of methanol / dichloromethane (0-10%). 230 mg of wax solid is obtained, and the yield was 57%. LCMS (ESI) m / z calculated for C16H27N2O8S+ (M+H)+ 407, found 407. Synthesis of biotin-labeled 2-deoxy-D-glucose: A solution of 328 mg of 2-deoxy-D-glucose (2DG, 2 mM), 768 mg of EDC (4 mM) and 22 mg of DMAP (0.02 mM) in dry N, N-dimethylformamide (DMF) (5 mL) was stirred at RT. 488 Attorney Docket No.9151.272.WO mg of biotin (2 mM) in dry DMF (5 mL) was added and the reaction mixture was stirred at RT overnight. Then the reaction mixture was concentrated under vacuum to remove DMF to afford a light-yellow wax. The wax was washed with 10.0 mL DCM and the solid was collected and dried under vacuum to afford 494 mg of light-yellow foam as the crude product of biotin-2DG with yield 50.5%. LCMS (ESI) m / z calculated for C16H26N2O7S+ (M+H)+ 390, found 391. Cell culture: Hep3B, HEK293, HEK293T, PC3, B16, CT26, 4T1, TRAMP-C2, AMPK- / -MEF were cultured in required medium supplied with 10% Fetal Bovine Serum (FBS) and 1% Penicillin / Streptomycin at 37 °C under 5 % CO2. Glucose starvation and glucose restoration: For glucose deprivation, cells were washed with PBS for twice and cultured in glucose-free DMEM supplied with dialyzed FBS for indicated time. The cells were stimulated by the addition of DMEM with glucose, 2DG, 3OMG, G6P, peptide, or cGAMP for 2h. Plasmid constructions: Full-length CDSs of human NSUN2 genes (GeneID: 54888; F1: NM_017755.6, transcript variant 1; F2: NM_001193455.2, transcript variant 2; F3: NR_037947.2, transcript variant 3) were amplified by PCR using human HEK293 cDNA and subcloned into pGEX-6P-1. The human NSUN2 mutants were generated based on the full- length NSUN2-F1 expression vector with Q5 Site-Directed Mutagenesis Kit (New England Biolabs) according to the manufacturer’s instructions. The corresponding primers used are as follows: NSUN2-F1 Forward (SEQ ID NO:36), 5ʹ-CGGAATTCATGGGGCGGCGTTCGCGGG-3ʹ; Reverse (SEQ ID NO:37) , 5ʹ-CCGCTCGAGTTACCGGGGTGGATGGACC-3ʹ). NSUN2-F2 Forward (SEQ ID NO:36), 5ʹ-CGGAATTCATGGGGCGGCGTTCGCGGG-3ʹ; reverse (SEQ ID NO:37), 5ʹ-CCGCTCGAGTTACCGGGGTGGATGGACC-3ʹ). NSUN2-F3 Forward (SEQ ID NO:38), 5ʹ-CGGAATTCATGGTGGTCAATCACGATGCC-3ʹ; reverse (SEQ ID NO:37), 5ʹ- CCGCTCGAGTTACCGGGGTGGATGGACC-3ʹ). NSUN2-Δ1-84 Forward (SEQ ID NO:39), 5ʹ-GGATCCCCGGAATTCAGCCACGCAAAAGAG -3ʹ; Reverse (SEQ ID NO:40) , 5ʹ- CTCTTTTGCGTGGCTGAATTCCGGGGATCC-3ʹ). NSUN2-Δ184-190 Forward (SEQ ID NO:41), 5ʹ-AAGATCTTAGATATGACCACACAGTTAATT -3ʹ; Attorney Docket No.9151.272.WO Reverse (SEQ ID NO:42), 5ʹ- AATTAACTGTGTGGTCATATCTAAGATCTT-3ʹ). NSUN2-Δ121-236 Forward (SEQ ID NO:43), 5ʹ-CAGCCACTGAGTTGGATGGTGGTCAACCAT-3ʹ; Reverse (SEQ ID NO:44), 5ʹ- ATGGTTGACCACCATCCAACTCAGTGGCTG-3ʹ). NSUN2-Δ1-28 Forward (SEQ ID NO:45), 5ʹ-GGATCCCCGGAATTCCGCGGCGAGGCGGG -3ʹ; Reverse (SEQ ID NO:46), 5ʹ- GCCCGCCTCGCCGCGGAATTCCGGGGATCC-3ʹ). NSUN2-Δ29-56 Forward (SEQ ID NO:47), 5ʹ-GAGGGTGGTGGAAAGATCGTGCCCGAGGGC -3ʹ; Reverse (SEQ ID NO:48), 5ʹ- GCCCTCGGGCACGATCTTTCCACCACCCTC-3ʹ). NSUN2-Δ57-84 Forward (SEQ ID NO:49), 5ʹ-TACCAGGAGCTCAAGAGCCACGCAAAAGAG-3ʹ; Reverse (SEQ ID NO:50), 5ʹ- CTCTTTTGCGTGGCTCTTGAGCTCCTGGTA-3ʹ. All plasmids were validated by DNA sequencing and prepared with the Fastfilter Plasmid Midi Kit (Omega Bio-tek). To clone NSUN2 or its mutant or TREX2 into mammalian expressing vector, full-length CDSs of human NSUN2-F1 (NM_017755.6) or TREX2 (NM_080701.4) were amplified by PCR using human HEK293 cDNA and subcloned into pFLAG-CMV2 vector (Sigma-Aldrich) or pCDH-blasticidin vector. The corresponding primers used are as follows: NSUN2-F1 Forward (SEQ ID NO:51), 5ʹ-CGGAATTCAATGGGGCGGCGGTCGCGGGG-3ʹ; Reverse (SEQ ID NO:52), 5ʹ-TCCGGTACCTTACCGGGGTGGATGGACCC-3ʹ. TREX2 Forward (SEQ ID NO:53), 5ʹ- GGGAATTCATGTCCGAAGCACCCCGGGC-3ʹ; Reverse (SEQ ID NO:54), 5ʹ- CCGCTCGAGTCAGGCCTCCAAGCTGGGG-3ʹ. Expression and purification of recombinant protein: For purifying recombinant NSUN2 expression, GST-tagged pGEX-6P-1 expression vectors encoding NSUN2-F1, NSUN2-F2, NSUN2-F3, NSUN2-Δ1-84, NSUN2-Δ184-190, NSUN2-Δ121-236, NSUN2-Δ1- 28, NSUN2-Δ29-56, or NSUN2-Δ57-84 mutants were transformed into Escherichia coli BL21 (DE3). The cells were grown in LB (Lysogeny broth) medium at 37 °C. When the culture reached an OD600 of 0.6, 1 mM IPTG was added. The culture was transferred to a shaking incubator at 20 °C for overnight. Recombinant proteins were then purified using Glutathione Sepharose® 4B and cleaved with PreScission protease according to the manufacturer’s Attorney Docket No.9151.272.WO instructions. Recombinant proteins were subjected to SDS-PAGE, followed by Coomassie brilliant blue staining (CBB) and immunoblotting to examine the purity of the recombinant proteins. The purified proteins were split and stored at -80 °C. Immunoblotting: For immunoblotting, whole cell lysates were prepared from the cells lysed with E1A buffer (50 mM HEPES, pH 7.6, 250 mM NaCl, 0.1% Nonidet P-40, 5 mM EDTA) supplemented with complete protease inhibitor cocktail (Roche, 04693132001). Cell lysates were subjected to SDS-PAGE and proteins were visualized by enhanced chemiluminescence according to the manufacturer’s instructions (Millipore). Biotin pull-down assay: Biotin-glucose pull-down assays were performed according to our previous studies (Hsu et al., 2021; Zhang et al., 2019). In brief, magic Dynabeads MyOne Streptavidin T1 (Thermal Fisher) was pre-incubated with free biotin or biotin-labeled glucose for 30 min at RT, and then incubated with cell lysates, recombinant proteins or peptides rotated overnight at 4 °C. The beads were washed with PBS for 4 times and analyzed by immunoblotting. Lentiviral infection with shRNAs or mammalian expressing vectors for gene knockdown and restoration: Lentiviral infection was performed based on our earlier studies (Chan et al., 2012; Yang et al., 2009). To generate lentivirus-producing cell lines, calcium phosphate was used to transfect with luciferase (shluc), target gene shRNA, virusGag-Pol packing vector (pPAX) and virus envelope glycoprotein expression vector (pMD.2G) in HEK293T cells. Supernatants containing virus particles were collected 48 h after transfection, filtered (0.45 µm), purified by centrifugation, and stored at -80 °C. Infections were carried out overnight by incubating cells with supernatants in the presence of 8 µg / mL Polybrene (Sigma-Aldrich). After viral infection, cells were selected by puromycin (3 µg / ml) for 7 days. The individual mission shRNAs kept in frozen bacterial glycerol were purchased from Sigma-Aldrich. For restoration of NSUN2-WT, NSUN2-Δ28, and TREX2 in NSUN2 knockdown cells, HEK293T were co-transfected with pCDH-NSUN2-WT, NSUN2-Δ28, and TREX2-blasticidin and package plasmids (pPAX / pMD.2G). After 48 h, virus containing supernatants were harvested to infect NSUN2 knockdown cells. All stably transfected cells were selected by blasticidin (5 µg / ml) for 7 days. Immunofluorescence and confocal microscopy: Cells grown on autoclaved coverslips were fixed with 4% paraformaldehyde (PFA) for 20 min and permeabilized with 0.4% Triton X-100 for 7 to 10 min and blocked with 5% BSA for 1 h. The primary antibody against dsDNA was applied onto the cells and incubated overnight at 4 °C. Cells then were washed with Attorney Docket No.9151.272.WO 1×PBS, incubated with a secondary antibody (Alexa 488 fluorescein-conjugated anti-mouse IgG) for 1 h at RT, and washed twice by 1×PBS. Coverslips were then mounted on a slide using one drop of mounting medium containing DAPI. The images of dsDNA were acquired using Olympus FV1200 Spectral Laser Scanning Confocal Microscope (Spada et al., 2019). RNA isolation and m5C Dot blot assay: Total RNA was extracted by using Quick- RNA™ Miniprep Kit (ZYMO Research) according to manufacturer’s manual. RNA samples were quantified by 2200 Tape Station (Agilent). For Dot blot assay, equal amounts of RNA were loaded onto the positive charged nylon transfer membrane (GE Healthcare). After UV crosslinking (Stratalinker® UV Crosslinker 1800) for 3 min at 254 nm, the membrane was blocked with 5% non-fat dried milk in PBS with 0.1% Tween-20 (PBST), followed by incubation with the primary rabbit anti-m5C antibody (CST, 28692S) and then peroxidase affinipure goat anti-Rabbit IgG (H+L) (Jacksonimmuno, 111-035-003) secondary antibody. m5C RNA levels were visualized by enhanced chemiluminescence (Millipore). Equal RNA loading was verified by methylene blue (MB, Sigma-Aldrich) staining. The intensity of Dot blot signal was quantified by ImageJ. Quantitative real time polymerase chain reaction (RT-qPCR): Total RNAs (0.5 to 1 µg) were subjected to reverse transcription with PrimeScript RT Master Mix (Takara, DRR036A). To determine relative mRNA level, RT-qPCR was performed using 2x SYBR Green qPCR Master Mix (BIMAKE, B21203) and gene expression was normalized with GAPDH. ΔΔCt method (Livak and Schmittgen, 2001) was used to indicate the relative expression level of corresponding genes. Primers used for RT-qPCR were listed in Table S4. In vitro methylation assays: To measure NSUN2 activity, the in vitro methylation assay by NSUN2 was performed as described previously (Tang et al., 2015). Briefly, 50 µl of reaction mixture containing 0.2 nM purified NSUN2 proteins, 0.01 nM RNA, and 1 µCi of3H-labeled S-adenosyl-L-methionine ([3H]SAM, ART 0288-250 µCi, American radiolabelled) in reaction buffer (5 mM Tris HCL [pH 7.5], 5 mM EDTA, 10% glycerol, 1.5 mM dithiothreitol, 5 mM MgCl2) supplemented with inhibitors (leupeptin [1 µg / ml], aprotinin [1 µg / ml], 0.5 mM phenylmethylsulfonyl fluoride, and RNasin [5 U / ml, Promega]) was incubated for 45 min at 37 °C. Unincorporated [3H]SAM in the reactions was removed by using Zymo-Spin IIICG Columns (ZYMO Research) and the incorporated radioactivity was measured by liquid scintillation counting. Native-PAGE assay and chemical crosslinking: Protein samples were prepared with Native Sample Buffer and subjected to Native-PAGE, followed by immunoblotting. For Attorney Docket No.9151.272.WO chemical crosslinking, protein samples were proceeded with Bismaleimide Crosslinkers (BMH, Thermo) according to the manufacturer’s instructions, followed by SDS-PAGE and immunoblotting. Colony formation assay, apoptosis assay and tumor sphere formation assay: For colony formation assay, cells (2x103) were plated into 12 well plates for 12 days. Cells were rinsed with PBS to remove the dead cells and stained with crystal violet, followed by incubating with 2% SDS. Absorption at 600 nm was measured to calculate the relative survival rate for each group. For apoptosis assay, cells were deprived with glucose for 22 h and then stimulated with DMEM medium with 5.5 mM glucose for 2 h. Then the cells were proceeded with the FITC Annexin V Staining Protocol (FITC Annexin V Apoptosis Detection Kit I, BD) to measure apoptosis. For in vitro tumor sphere forming assay, 4x103cells were seeded in the ultra-low attachment 6-well plate (Corning Life Science) and cultured in tumor sphere-forming medium (DME / F12 supplemented with 5 µg / ml insulin, 0.4% BSA, 20 ng / ml human epidermal growth factor, 10 ng / ml basic fibroblast growth factor, and 1 X B-27™ Supplement [50X, Gibco]). Cells were incubated at 37 °C for 12 days and spheres larger than 50 µm were counted. RNA-seq: Total RNA was isolated from shluc and shNSUN2 Hep3B cells, which were either glucose-starved for 6 h or glucose-starved for 4 h and then add-back glucose for 2 h, by using Quick-RNA™ Miniprep Kit (ZYMO Research) according to manufacturer’s procedures. RNA samples were quantified by 2200 Tape Station (Agilent) and sent to GENEWIZ for RNA- seq using Illumina HiSeq 2x150 bp sequencing. Three independent biological replicates were performed for RNA-seq. RNA-IP and gene-specific m5C qPCR: RT-qPCR was performed to assess the relative abundance of the selected mRNA in m5C antibody immunoprecipitation (IP) samples and input samples. Briefly, total RNA was isolated with Quick-RNA™ Miniprep Kit.500 ng RNA was used as an input sample and the remaining RNA was used for m5C IP. 100 ^ ^g of RNA was diluted into 500 μl IP buffer (150 mM NaCl, 0.1% NP-40, 10 mM Tris, pH 7.4, 100 U RNase inhibitor) and incubated with m5C antibody at 4 °C for 2 h. Dynabeads® Protein A coated with BSA was added into the reaction solution and rotated for 2 h at 4 °C. After washing by IP buffer with RNase inhibitors four times, the m5C IP portion was eluted with elution buffer (5 mM Tris-HCL [pH 7.5], 1 mM EDTA, 0.05% SDS, and 4 μl Proteinase K [20 mg / ml]). The final eluted mRNA was concentrated with an RNA Clean & Concentrator-5 kit. The same amounts of the concentrated IP RNA or input RNA from each sample were used for the cDNA library. The mRNA expression was determined by the number of amplification cycles (Cq). Attorney Docket No.9151.272.WO The relative m5C levels in gene were calculated by the m5C levels (m5C IP) normalized with the expression of each gene from the input sample. For mapping assay of the NSUN2 fragments binding to TREX2 mRNA, similar to the procedure above RNA-IP were performed using anti- NSUN2 antibody along with various NSUN2 truncated proteins, followed by RT-qPCR analysis of TREX2 mRNA. RNA decay assay: Cells were seeded in 6-well plates and incubated overnight at 37 °C, treated with Actinomycin D (2 μg / ml, A1410, Sigma-Aldrich) for different time points, and harvested for the collection of RNA samples. TREX2 mRNA levels against GAPDH RNA levels were analyzed by RT–qPCR. The half-life of TREX2, ACTIN and NSUN2 mRNA normalized with GAPDH was then measured with their levels at t = 0 as 100% according to the previous study (Zhang et al., 2012). Detection of cGAMP and IFN-β levels by Enzyme-Linked Immunosorbent assay (ELISA): To detect cGAMP levels in cells, treated cells were lysed in M-PER™ Mammalian Protein Extraction Reagent (Thermo Fisher) and the levels of cGAMP in cell lysates were measured by 2′3′-cGAMP competitive ELISA assay Kit (501700, Cayman) according to manufacturer’s protocol and previous study (Yu et al., 2020). To detect IFN-β levels in treated cells, cell culture media were centrifuged at 2,000 x g for 10 mins to remove debris and collected supernatants for assessing IFN-β levels by human IFN-β ELISA Kit (ab278127, Abcam) according to manufacturer’s protocol. Animal studies: Animals were housed in a specific-pathogen-free facility under standard condition. (6-week-old) were purchased from Charles River Laboratories (n = 5 for each group). For in vivo xenograft tumorigenesis assays, Hep3B or PC3 cells (1x106) were injected subcutaneously (s.c.) into athymic nude mice (Crl:NU(NCr)-Foxn1nu, Code 490, male). In syngeneic mouse model (allograft) study, B16 or TRAMP-C2 cells (5x105) were injected s.c. into C57BL / 6 (Code 027, male) mice; CT26 (5x105) or 4T1 cells (1x104) were injected s.c. into BALB / c (NCI BALB-cAnNCr, Code 555, female) mice. The dose and dosing schedule used with anti-mouse PD-L1 (Clone 10F.9G2) or rat IgG2b isotype control antibodies was 100 or 200 μg per intra-peritoneally administered at 3-to-5-day intervals. Tumor was measured by Caliper for length and width, and tumor volume was determined based on the formula: V = (Length x Width x Width) / 2. Animals were housed in a specific-pathogen-free facility under standard condition. Immunohistochemistry: Formalin-fixed, paraffin-embedded tumor tissue samples were sectioned at 4 μm. After deparaffinization and hydration, the sections were heated at 95 ^C in Attorney Docket No.9151.272.WO citrate buffer (pH 6.0) for epitope retrieval, quenched with hydrogen peroxide blocking reagent to abolish endogenous peroxidase. To block nonspecific antibody binding, sections were incubated in blocking solution (10% normal goat serum in PBST) at RT for 1 h. Primary antibodies were incubated overnight at 4 °C. Secondary antibodies were incubated for 2 h at RT. The DAB Substrate Kit was used for visualization according to manufacturer’s protocol. Finally, sections were counterstained with acid hematoxylin solution (12 min) and Scott's bluing reagent (5 min), dehydrated in an ascending alcohol series up to 100%, cleared with xylene (5 min), and coverslipped by Tissue-Tek Glas™ mounting medium. Quantification and statistical analysis: All quantification were performed using ImageJ software. The schematic representations (FIG.1 panels A, D, F, H, and J, and FIG.4 panel O) were created using PowerPoint. The heatmap (FIG. 4 panel A) was created using Excel. The illustration of the mechanism (FIG.7 panel H) were created using BioRender. All the other graphs and Statistical Analysis were performed using GraphPad.Prism 7. Data were presented as mean ± SD. Statistical significance for pairwise comparison of variables were calculated using two-tailed unpaired Student’s t-test. P values were calculated using a two-way ANOVA for cell growth curve, tumor volume changes and RNA decay assay. For all analyses, p < 0.05 were regarded as statistically significant. *, p < 0.05. **, p < 0.01. ***, p < 0.001. NS, non-significant. The 95% confidence interval were used for all general statistical analyses. For mass spectrometry analysis and RNA-seq, samples were processed in random order and experimenters were blinded to experimental conditions. Data shown are representative of three independent experiments (biological replicates).

[0002] Attorney Docket No.9151.272.WO TABLES Table 1: Candidate Targets Binding with Glucose from Mass Spectrometry Analysis (Total Spectrum Count), Related to FIG.1. Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No. 9151.272.WO Table 2. Candidate Targets Containing Motif (RRSR; SEQ ID NO:34) By Blasting NSUN2 N28 Peptide, Related to FIG.1. Sequences shown in Table 2 include: RRSR (SEQ ID NO:34) GRRSR (SEQ ID NO:57) GRRSRSYGRR (SEQ ID NO:58) RRSRGR (SEQ ID NO:59) RRSRSR (SEQ ID NO:60) RRSRSTSRERR (SEQ ID NO:61)

[0003] Attorney Docket No.9151.272.WO Table 3. Candidate Targets Regulated by Glucose in a NSUN2-Dependent Manner from RNA-seq, Related to FIG.4. Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Table 4. Primers Used for RT-qPCR in Examples. Attorney Docket No.9151.272.WO Table 5: Non-limiting Resources Table. Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO Attorney Docket No.9151.272.WO The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

Attorney Docket No.9151.272.WO THAT WHICH IS CLAIMED IS:

1. A method of reducing oncogenic activity in a cancer cell, comprising contacting the cell with an effective amount of an inhibitor of NSUN2 (e.g., an inhibitor of NSUN2 activation, e.g., an inhibitor of NSUN2 activity, e.g., an inhibitor of NSUN2 binding by glucose).

2. The method of claim 1, wherein the reduced oncogenic activity of the cancer cell comprises Warburg effect, cancer stem cell maintenance, cancer cell proliferation, and / or cancer treatment resistance (e.g., resistance to immunotherapy).

3. The method of claim 1 or 2, wherein the oncogenic activity of the cancer cell reduced comprises resistance to immunotherapy by a cancer cell.

4. The method of any one of claims 1-3, wherein the inhibitor of NSUN2 comprises a polypeptide comprising an amino acid sequence having at least 90% identity to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33) or a compound, composition or combination comprising the same.

5. The method of any one of claims 1-4, wherein the inhibitor of NSUN2 comprises the amino acid sequence RRSR (SEQ ID NO:34).

6. The method of any one of claims 1-5, wherein the contacting of the cancer cell with the inhibitor of NSUN2 inhibits NSUN2 activity in the cancer cell (e.g., inhibits NSUN2 activity in the cancer cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein, e.g., as compared to a cancer cell not contacted with the inhibitor).

7. The method of any one of claims 1-6, wherein the contacting of the cancer cell with the inhibitor of NSUN2 reduces TREX2 expression and / or activity in the cancer cell (e.g., reduces TREX2 expression and / or activity in the cancer cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,Attorney Docket No.9151.272.WO 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein, e.g., as compared to a cancer cell not contacted with the inhibitor).

8. The method of any one of claims 1-7, wherein the contacting of the cancer cell with the inhibitor of NSUN2 enhances cGAS / STING expression and / or activity in the cancer cell (e.g., enhances cGAS / STING expression and / or activity in the cancer cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more or any value or range therein, e.g., as compared to a cancer cell not contacted with the inhibitor).

9. The method of any one of claims 1-8, wherein the contacting of the cancer cell with the inhibitor of NSUN2 does not affect glucose metabolism of the cancer cell.

10. The method of any one of claims 1-9, wherein the cancer cell is in a human subject.

11. A method of inhibiting binding of glucose and NSUN2 in a cell, comprising: contacting the cell with an effective amount of a polypeptide comprising an amino acid sequence having at least 90% identity to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33) or a compound, composition or combination comprising the same, thereby inhibiting binding of glucose and NSUN2 in the cell.

12. The method of claim 11, wherein the contacting of the cell with the polypeptide or compound, composition or combination comprising the same inhibits NSUN2 expression and / or activity in the cell (e.g., inhibits NSUN2 activity in the cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein, e.g., as compared to a cell not contacted with the polypeptide or compound, composition or combination).

13. The method of claim 11 or 12, wherein the contacting of the cell with the polypeptide or compound, composition or combination comprising the same reduces TREX2 expression and / or activity in the cell (e.g., reduces TREX2 expression and / or activity in the cell by atAttorney Docket No.9151.272.WO least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein, e.g., as compared to a cell not contacted with the polypeptide or compound, composition or combination).

14. The method of any one of claims 11-13, wherein the contacting of the cell with the polypeptide or compound, composition or combination comprising the same enhances cGAS / STING expression and / or activity in the cell (e.g., enhances cGAS / STING expression and / or activity in the cell by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein, e.g., as compared to a cell not contacted with the polypeptide or compound, composition or combination).

15. The method of any one of claims 11-14, wherein the cell is a cancer cell.

16. The method of any one of claims 11-15, wherein the cell is in a human subject.

17. A method of treating cancer in a human subject in need thereof (e.g., a human subject having or suspected of having cancer, e.g., a cancer patient), comprising administering to the subject an effective amount of an inhibitor of NSUN2 (e.g., an inhibitor of NSUN2 activation, e.g., an inhibitor of NSUN2 activity, e.g., an inhibitor of NSUN2 binding by glucose), thereby treating the cancer in the subject.

18. A method of increasing sensitivity of cancer cells to immunotherapy in a human subject in need thereof (e.g., a human subject having or suspected of having cancer), comprising administering to the subject an effective amount of an inhibitor of NSUN2 (e.g., an inhibitor of NSUN2 activation, e.g., an inhibitor of NSUN2 activity, e.g., an inhibitor of NSUN2 binding by glucose), thereby increasing sensitivity of the cancer cells to immunotherapy in the subject.

19. A method of increasing efficacy of immunotherapy in treating cancer in a human subject in need thereof (e.g., a human subject having or suspected of having cancer, e.g., aAttorney Docket No.9151.272.WO human subject receiving immunotherapy treatment), comprising administering (co- administering) to the subject receiving immunotherapy treatment an effective amount of an inhibitor of NSUN2 (e.g., an inhibitor of NSUN2 activation, e.g., an inhibitor of NSUN2 activity, e.g., an inhibitor of NSUN2 binding by glucose).

20. The method of any one of claims 17-19, wherein the inhibitor of NSUN2 comprises a polypeptide comprising an amino acid sequence having at least 90% identity to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33) or a compound, composition or combination comprising the same.

21. The method of any one of claims 17-20, wherein the inhibitor of NSUN2 comprises the amino acid sequence RRSR (SEQ ID NO:34).

22. The method of any one of claims 17-21, wherein the administering of an effective amount of the inhibitor of NSUN2 inhibits NSUN2 activity in the cancer (e.g., inhibits NSUN2 activity in the cancer (e.g., in one or more cancer cells of the cancer) by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein, e.g., as compared to a cancer (e.g., one or more cancer cells of the cancer) in a human subject having the cancer and having not been administered the inhibitor of NSUN2).

23. The method of any one of claims 17-22, wherein the administering of an effective amount of the inhibitor of NSUN2 reduces TREX2 expression and / or activity in the cancer (e.g., reduces TREX2 expression and / or activity in the cancer (e.g., in one or more cancer cells of the cancer) by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein, e.g., as compared to a cancer (e.g., one or more cancer cells of the cancer) in a human subject having the cancer and having not been administered the inhibitor of NSUN2).

24. The method of any one of claims 17-23, wherein the administering of an effective amount of the inhibitor of NSUN2 enhances cGAS / STING expression and / or activity in the cancer (e.g., enhances cGAS / STING expression and / or activity in the cancer (e.g., in one orAttorney Docket No.9151.272.WO more cancer cells of the cancer) by at least about 5% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein, e.g., as compared to a cancer (e.g., one or more cancer cells of the cancer) in a human subject having the cancer and having not been administered the inhibitor of NSUN2).

25. The method of any one of claims 1-11 or 15-25, wherein the cancer is breast cancer, prostate cancer, intestinal cancer (e.g., colon cancer), skin cancer (e.g., melanoma), liver cancer, and / or lung cancer, pancreatic cancer, head and neck cancer, brain cancer (e.g. glioblastoma), blood cancer (e.g. lymphoma), bladder cancer, or ovarian cancer.

26. The method of any one of claims 17-25, further comprising administering to the subject one or more anti-cancer therapeutic agent and / or applying an anti-cancer treatment.

27. The method of claim 26, wherein the anti-cancer therapeutic agent or treatment consists of any one of immunomodulatory agents, anti-inflammatory agents, immunotherapy treatment (e.g., immunocheckpoint blockade agents), a surgical procedure, radiation, or in any combination thereof.

28. The method of claim 26 or 27, wherein the anti-cancer therapeutic agent or treatment comprises a cancer treatment selected from the group consisting of Doxorubicin, cyclophosphamide, 5-flurouracil, vinorelbine, pembrolizumab, nivolumab, durvalumab, Paclitaxel, Docetaxel, Oligomycin, JQ1, emodin, metformin, shikonin, physcion (6PGD inhibitor), AICAR, oxythiamine, leflunomide, lonidamine, polydatin, honokiol, dehydropiandrosterone (DHEA), venetoclax (ABT-199, Bcl-2 inhibitor), navitoclax (ABT- 263), A-1331852 (Bcl-xL inhibitor), ABT-737, S63845 (Mcl-1 inhibitor), immunotherapy treatment (e.g., anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-PD-1, anti-OX40, anti-GITR, anti-4-1BB, anti-CD47, anti-SIRP ^, or the like) and any combination thereof.

29. The method of any of claims 17-28, wherein the inhibitor is administered in a range of about 10 mg / Kg to about 100 mg / Kg.Attorney Docket No.9151.272.WO 30. The method of any one of claims 17-29, wherein the human subject has previously received immunotherapy treatment.

31. The method of 17-30, wherein the cancer was previously resistant (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any value or range therein) to previously received immunotherapy treatment.

32. The method of any one of claims 17-31, wherein the administering of the inhibitor of NSUN2 does not affect glucose metabolism in the subject.

33. The method of any one of claims 1, 3, 5-10 or 18-32, wherein the immunotherapy treatment is antagonist and / or agonist antibody therapy, such as anti-PD-L1, anti-PD-L2, anti- CTLA-4, anti-PD-1, anti-OX40, anti-GITR, anti-4-1BB, or the like.

34. The method of any one of claims 17-33, wherein the inhibitor is administered topically (e.g., direct application), intravenously, cutaneously, subcutaneously, intraperitoneally, intra-arterially, intratumorally, intrathecally, intramuscularly, orally (e.g., by oral tablet or capsule), intranasally, sublingually, via inhalation, in an implant, in a matrix, in a gel, or any combination thereof.

35. A compound, composition or combination comprising a polypeptide comprising an amino acid sequence having at least 90% identity to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33).

36. A non-naturally occurring polypeptide (e.g., a synthetic polypeptide) comprising an amino acid sequence having at least 90% identity to the amino acid sequence MGRRSRGRRLQQQQRPEDAEDGAEGGGK (SEQ ID NO:33).

37. The polypeptide of claim 30 or compound, composition, combination of claim 36, for use in any one of the methods of claims 1-34.Attorney Docket No.9151.272.WO 38. The polypeptide, compound, composition or combination of any one of claims 35-37, further comprises a pharmaceutically acceptable carrier (e.g., a pharmaceutical formulation).

39. A kit comprising the polypeptide, compound, composition or combination of any one of claims 35-38, and instructions for use.

40. Use of polypeptide, compound, composition or combination of any one of claims 35- 38 in reducing resistance to immunotherapy in a cancer cell, reducing oncogenic activity of a cancer cell, reducing Warburg effect in a cancer cell, inhibiting binding of glucose and NSUN2 in a cell, inhibiting NSUN2 activity in a cell, treating cancer, increasing sensitivity of a cancer cell to immunotherapy, and / or increasing efficacy of immunotherapy in treating cancer.

41. Preparation of a medicament for use comprising the polypeptide, compound, composition or combination of any one of claims 35-38.

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