Tumor immune microenvironment regulation type photo-activated ferroptosis nanoparticles as well as preparation method and application thereof

Abstract

The invention discloses tumor immune microenvironment regulation type photo-activated ferroptosis nanoparticles as well as a preparation method and application thereof, and relates to the technical field of biological medicines. The preparation method comprises the following steps: dissolving albumin and ferritin in water, adjusting the pH value to be alkaline, adding a photosensitizer and lipoic acid, mixing, adding a solvent, carrying out a mixing reaction, adding a cross-linking agent, continuing the reaction, and carrying out centrifugation and drying treatment to obtain the tumor immune microenvironment regulation type light-activated ferroptosis nanoparticles. The tumor immunosuppression microenvironment is reversed by inducing tumor cell ferroptosis, activating dendritic cells and regulating M1-type polarization of M2-type tumor-related macrophages, so that the tumor immunotherapy effect is enhanced.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a tumor immune microenvironment regulating light-activated ferroptosis nanoparticle, and a preparation method and application thereof. Background Art

[0002] Tumor immunotherapy is an effective anti-tumor strategy developed in recent years, which activates the body's own immune system to identify and kill tumors. However, due to the low immunogenicity of solid tumors and the existence of an immunosuppressive tumor microenvironment, tumor immunotherapy has a low response rate and poor efficacy in some patients. Dendritic cells (DCs) and macrophages, as the main effector cells of the innate immune response, play a key role in triggering anti-tumor immune responses. They are also an important link in connecting the body's innate immune response and adaptive immune response. They are considered to be one of the key targets for enhancing the effect of tumor immunotherapy.

[0003] Ferroptosis-inducing drugs utilize iron-dependent lipid peroxide overaccumulation to induce immunogenic death of tumor cells, release damage-associated molecular patterns as "immune stimulatory signals", promote DCs maturation, and activate cytotoxic CD8 + T lymphocytes react and initiate anti-tumor immune responses. In addition, the ferroptosis of tumor cells also plays an important role in regulating the polarization of tumor-associated macrophages (TAMs) from M2 to M1 phenotypes. The above studies show that ferroptosis-assisted tumor immunotherapy will become a new strategy for tumor immunotherapy. With the development of nanotechnology, various iron-based nanomaterials, including iron oxide nanoparticles, amorphous iron nanoparticles, and iron-organic framework materials, have been widely used in tumor ferroptosis therapy research. However, excessive use of iron-based nanomaterials may increase adverse health risks due to liver damage and chronic kidney disease. Therefore, it is necessary to develop a new tumor immune microenvironment-regulated light-activated ferroptosis nanoparticle to reshape the tumor immune microenvironment and enhance the effect of tumor immunotherapy. Summary of the invention

[0004] The purpose of the present invention is to provide a tumor immune microenvironment regulated light-activated ferroptosis nanoparticle and its preparation method and application to solve the problems existing in the above-mentioned prior art. The tumor immune microenvironment regulated light-activated ferroptosis nanoparticle reverses the tumor immunosuppressive microenvironment by inducing tumor cell ferroptosis, activating DCs and regulating the M1 polarization of M2 TAMs, thereby enhancing the tumor immunotherapy effect.

[0005] Ferritin is a common iron storage protein in organisms. The iron in it can be converted into Fe 2+. Using ferritin as a drug that induces ferroptosis provides a possibility to avoid the toxicity problem caused by excessive exogenous metallic iron. Studies have shown that under appropriate laser irradiation, the reactive oxygen species (ROS) produced by photosensitizers can destroy the ferritin structure, accelerate the release of iron in ferritin, increase the intracellular iron content, and activate ferroptosis of tumor cells. Other studies have shown that the ROS produced by photosensitizers under laser irradiation can not only induce DCs maturation, but also regulate the M1 polarization of M2-TAMs.

[0006] Tumor cells, DCs and TAMs interact closely with each other, and drug delivery strategies that simultaneously target and regulate “tumor cells, DCs and TAMs” may become a new entry point for enhancing the efficacy of anti-tumor immunity. However, ferroptosis-inducing drugs may indiscriminately induce the death of tumor cells, DCs and TAMs in the tumor microenvironment. Therefore, how to achieve ferroptosis drugs killing tumor cells while activating DCs and TAMs, synergistically regulating “DCs, TAMs and tumor cells”, and reshaping the tumor immune microenvironment may become the key to enhancing the efficacy of immunotherapy for solid tumors.

[0007] The present invention uses ferritin and albumin as nano drug carriers, and prepares a tumor immune microenvironment-regulated light-activated ferroptotic nanoparticle by co-loading lipoic acid and photosensitizer. The light-activated nanoparticle can generate ROS under near-infrared laser irradiation, accelerate the degradation of ferritin in the nanoparticle to release Fe 3+ , induces ferroptosis of tumor cells; Fe 3+ Under the action of high concentration of reduced glutathione (GSH) in tumor cells, it can be converted into Fe with ferroptosis induction. 2+ , inducing immunogenic death of tumor cells; using lipoic acid to promote Fe 3+ -Fe 2+ The photoactivated nanoparticles can enhance the cumulative effect of iron ions in tumor cells and synergistically enhance the effect of ferroptosis. The immunogenic death of tumor cells based on ferroptosis can indirectly promote the maturation of DCs and regulate the M1 polarization of M2 TAMs. At the same time, the ROS produced by the photoactivated nanoparticles can directly activate DCs and regulate the M1 polarization of M2 TAMs. The photoactivated ferroptosis nanoparticles can achieve the "one stone, three birds" strategy of synergistically regulating "tumor cells, DCs and TAMs", reverse the tumor immunosuppressive microenvironment, and have a significant anti-tumor immunotherapy effect.

[0008] Based on this, the present invention provides the following solutions:

[0009] The present invention provides a method for preparing tumor immune microenvironment regulated light-activated ferroptosis nanoparticles, comprising the following steps:

[0010] Albumin and ferritin are dissolved in water, and the pH is adjusted to alkaline before adding a photosensitizer and lipoic acid, and then a solvent is added after mixing to carry out a mixing reaction, and then a cross-linking agent is added. After continuing the reaction, the reaction is centrifuged and dried to obtain the tumor immune microenvironment regulating light-activated ferroptosis nanoparticles.

[0011] Furthermore, the photosensitizer is indocyanine green or neoindocyanine green; and / or

[0012] The cross-linking agent is glutaraldehyde.

[0013] The CAS number of indocyanine green is 3599-32-4, and the CAS number of neoindocyanine green is 172616-80-7.

[0014] Furthermore, the mass ratio of the albumin, the ferritin, the lipoic acid and the photosensitizer is 15:5:2.5:0.5.

[0015] Furthermore, the solvent is anhydrous ethanol.

[0016] Furthermore, adjusting the pH to be alkaline means adjusting the pH to 9.0.

[0017] The present invention also provides a tumor immune microenvironment regulating light-activated ferroptosis nanoparticle prepared according to the above preparation method.

[0018] The present invention also provides the use of the above-mentioned tumor immune microenvironment regulating light-activated ferroptosis nanoparticles in the preparation of tumor immunotherapy drugs.

[0019] Furthermore, the drug reverses the tumor immunosuppressive microenvironment by inducing ferroptosis of tumor cells, activating DCs, and regulating the M1 polarization of M2 TAMs.

[0020] The present invention also provides a tumor immunotherapy drug, the active ingredient of which includes the above-mentioned tumor immune microenvironment regulating light-activated ferroptosis nanoparticles.

[0021] Furthermore, the tumor immunotherapy drug also includes pharmaceutically acceptable excipients.

[0022] The present invention discloses the following technical effects:

[0023] The present invention uses albumin and ferritin as nano drug carriers, and prepares a tumor immune microenvironment regulated light-activated ferroptosis nanoparticle by co-loading lipoic acid and a photosensitizer. The nano drug can avoid the toxicity problem caused by excessive exogenous metals, strengthen the cumulative effect of iron ions in tumor cells, and synergistically enhance the ferroptosis induction effect.

[0024] The photosensitizer in the nanoparticles of the present invention can generate light-activated ROS under near-infrared laser irradiation, accelerate the degradation of ferritin in the nanoparticles to release iron ions, induce ferroptosis-based immunogenic death of tumor cells, thereby indirectly promoting DCs maturation and regulating the M1 polarization of M2 TAMs; in addition, the ROS generated by the light-activated nanoparticles can directly activate DCs and regulate the M1 polarization of M2 TAMs, realize the synergistic mechanism of dual regulation of DCs and TAMs, initiate anti-tumor immune response, and reverse the tumor immunosuppressive microenvironment.

[0025] The nanoparticles of the present invention can selectively kill tumor cells in the tumor microenvironment, activate DCs and TAMs, and realize the "one stone, three birds" tumor immunotherapy strategy of synergistically regulating "DCs, TAMs and tumor cells". BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0027] Figure 1 The particle size and Zeta potential stability of the nanoparticles prepared in the present invention are investigated;

[0028] Figure 2 The toxicity test results of the nanoparticles of the present invention on 4T1 mouse breast tumor cells, DC2.4 cells and RAW264.7 cells under near-infrared laser irradiation;

[0029] Figure 3 The effect of the immunogenic death of tumor cells based on ferroptosis induced by the nanoparticles of the present invention on the maturation of BMDCs;

[0030] Figure 4 The results of the polarization experiment on M2-BMDMs cells by the nanoparticles of the present invention are shown in FIG.

[0031] Figure 5 Comparison results of tumor tissue tumor weight in different treatment groups;

[0032] Figure 6 The results of the analysis of the proportion of DCs in mouse tumors after the nanoparticles of the present invention were injected into mice bearing breast cancer 4T1 tumors;

[0033] Figure 7 These are the results of analyzing the proportion of M2 TAMs in mouse tumors after the nanoparticles of the present invention were injected into mice bearing breast cancer 4T1. DETAILED DESCRIPTION

[0034] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0035] It should be understood that the terms described in the present invention are only for describing a particular embodiment and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0036] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0037] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to the skilled artisan. The present invention description and examples are exemplary only.

[0038] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0039] The albumin used in the following examples was purchased from Beijing Solebow Technology Co., Ltd., and the ferritin was purchased from Sigma.

[0040] Example 1

[0041] A method for preparing tumor immune microenvironment-regulated light-activated ferroptosis nanoparticles comprises the following steps:

[0042] (a) Weigh 15 mg of albumin and 5 mg of ferritin and add them to 1 mL of pure water, add NaOH solution to adjust the pH to 9.0, then add 100 μL of 25 mg / mL lipoic acid dimethyl sulfoxide solution and 100 μL of 5 mg / mL indocyanine green (or neoindocyanine green) dimethyl sulfoxide solution, and stir to react for 15 min;

[0043] (b) After the stirring reaction is completed, 4 mL of anhydrous ethanol is added and reacted for 3 h, then 20 μL of 80 mg / mL glutaraldehyde aqueous solution is added, and the stirring reaction is continued for 12 h. The mixture is centrifuged at 2500 rpm for 20 min using an ultrafiltration tube, and freeze-dried to obtain tumor immune microenvironment-regulated light-activated ferroptosis nanoparticles (also named indocyanine green & lipoic acid @ ferritin & albumin nanoparticles).

[0044] The stability of tumor immune microenvironment-regulated photoactivated ferroptosis nanoparticles in 10% serum PBS (pH = 7.4) buffer solution was investigated using a Malvern particle size analyzer. Figure 1 As shown. Figure 1 It can be seen that the prepared tumor immune microenvironment regulated light-activated ferroptosis nanoparticles have good stability in the medium and can maintain a stable particle size distribution and potential distribution within 72 hours.

[0045] Comparative Example 1

[0046] (a) Weigh 15 mg of albumin and 5 mg of ferritin and add them to 1 mL of pure water. Add NaOH solution to adjust the pH to 9.0, then add 100 μL of 5 mg / mL indocyanine green dimethyl sulfoxide solution and stir for 15 min.

[0047] (b) After the stirring reaction was completed, 4 mL of anhydrous ethanol was added and reacted for 3 h, and then 20 μL of 80 mg / mL glutaraldehyde aqueous solution was added and the stirring reaction was continued for 12 h. The mixture was centrifuged at 2500 rpm for 20 min using an ultrafiltration tube and freeze-dried to obtain indocyanine green@ferritin & albumin nanoparticles.

[0048] Comparative Example 2

[0049] (a) Weigh 20 mg of albumin and add it to 1 mL of pure water. Add NaOH solution to adjust the pH to 9.0, then add 100 μL of 5 mg / mL indocyanine green dimethyl sulfoxide solution, and stir to react for 15 min.

[0050] (b) After adding 4 mL of anhydrous ethanol and reacting for 3 h, 20 μL of an 80 mg / mL glutaraldehyde aqueous solution was added, and the reaction was continued with stirring for 12 h. The mixture was centrifuged at 2500 rpm for 20 min using an ultrafiltration tube, and indocyanine green nanoparticles were obtained after freeze-drying.

[0051] Example 2

[0052] Toxicity experiments on 4T1 mouse breast tumor cells, DC2.4 cells, and RAW264.7 cells were conducted under near-infrared laser irradiation, as detailed below:

[0053] Experimental methods:

[0054] 4T1 tumor cells were cultured at a rate of 5×103 The cells were evenly plated in a 96-well plate at a density of 100 μg / well. After 24 hours of culture, the original culture medium was removed and the cells were divided into free indocyanine green group, indocyanine green nanoparticle group, indocyanine green@ferritin & albumin nanoparticle group and indocyanine green & lipoic acid@ferritin & albumin nanoparticle group. The drugs in each experimental group were added at an indocyanine green concentration of 20 μg / mL. After incubation for 4 hours, the culture medium was discarded. The cells in each experimental group were treated with 1 w / cm 2 After laser irradiation (808 nm, 1 min), the cells were cultured for 24 h and the cell survival rate was detected by CCK8 method.

[0055] The toxicity experimental study methods for DC2.4 cells and RAW264.7 cells are the same as above.

[0056] The experimental results are as follows Figure 2 As shown by Figure 2 As we know, at 1w / cm 2 Under the action of laser irradiation (808nm, 1min), the results of cytotoxicity of each group of drugs on 4T1 cells showed that the cell survival rates of the free indocyanine green group and the nanoparticle group containing indocyanine green were reduced, among which the cell survival rate of the indocyanine green & lipoic acid @ ferritin & albumin nanoparticle group was significantly reduced (about 30%). This shows that indocyanine green & lipoic acid @ ferritin & albumin nanoparticles can effectively induce ferroptosis of tumor cells under the action of laser. 2 Under the action of laser irradiation (808nm, 1min), after treatment with the drug group of indocyanine green & lipoic acid @ ferritin & albumin nanoparticles, the cell survival rates of DC2.4 cells and RAW264.7 cells were all above 80%. The above results show that indocyanine green & lipoic acid @ ferritin & albumin nanoparticles can selectively kill tumor cells, providing a possibility for realizing the tumor immunotherapy strategy of coordinated regulation of "DCs, TAMs and tumor cells".

[0057] Example 3

[0058] Experiment on the effect of ferroptosis-based immunogenic death of tumor cells induced by the nanoparticles of the present invention on the maturation of BMDCs:

[0059] Experimental methods:

[0060] (1) 4T1 tumor cells were cultured at a rate of 2×10 5 The cells were evenly plated in a 12-well plate at a density of 100 μg / well. After 24 hours of culture, the original culture medium was removed and the cells were divided into PBS group, free indocyanine green group, indocyanine green nanoparticle group, indocyanine green@ferritin & albumin nanoparticle group and indocyanine green & lipoic acid@ferritin & albumin nanoparticle group. Drugs were added to each experimental group at an indocyanine green concentration of 20 μg / mL, and the culture medium was discarded after incubation for 4 hours. The cells in each experimental group were treated with 1 w / cm2 After laser irradiation (808 nm, 1 min), the cells were cultured for 24 h.

[0061] (2) BMDCs were cultured at a rate of 1×10 6 The cells were evenly plated in a 12-well plate at a density of 5×10 cells / well. After incubation for 2 hours, the supernatant of the 4T1 cells cultured for 24 hours after laser irradiation in step (1) was collected and added to BMDCs. At the same time, the tumor cells cultured for 24 hours after laser irradiation in step (1) were collected and added to BMDCs. 4 The cells were re-plated into each well containing BMDCs at a density of 100 cells / well. After 24 h of co-culture, BMDCs were collected for staining with different fluorescent-labeled antibodies and detected by flow cytometry. The results are shown in Figure 3 shown.

[0062] Depend on Figure 3 It can be seen that compared with the PBS group, after BMDCs were co-incubated with 4T1 cells irradiated by each nanogroup laser, CD11c + CD80 + CD86 + The proportion of BMDCs increased significantly, among which the CD11c + CD80 + CD86 + The proportion of BMDCs increased the most (about 66%), indicating that ICG & LA@Ferritin & Albumin NPs can mediate the maturation of BMDCs through ferroptosis-based immunogenic death of tumor cells.

[0063] Example 4

[0064] Experimental study on polarization of BMDMs cells by nanoparticles of the present invention:

[0065] Experimental methods:

[0066] BMDMs were cultured at a rate of 1×10 6 The cells were evenly plated in a 12-well plate at a density of 100 μg / well and cultured overnight. After adding 40 ng / mL of IL-4 and culturing for 24 hours, the original culture medium was removed and the cells were divided into PBS group, free indocyanine green group, indocyanine green nanoparticle group, indocyanine green@ferritin & albumin nanoparticle group and indocyanine green & lipoic acid@ferritin & albumin nanoparticle group. The drugs of each experimental group were added according to the indocyanine green concentration of 20 μg / mL. After incubation for 4 hours, the culture medium was discarded. The cells in each experimental group were subjected to (808 nm, 1 min) 1 w / cm 2 After laser irradiation, the culture was continued for 24 h, and BMDMs were collected for staining with different fluorescent-labeled antibodies and detected by flow cytometry. Figure 4 shown.

[0067] Depend on Figure 4 As far as we know, compared with the PBS group, the F4 / 80 + CD206 + The proportion of BMDMs was significantly reduced in the indocyanine green@ferritin & albumin nanoparticle group and the indocyanine green & lipoic acid@ferritin & albumin nanoparticle group F4 / 80 + CD206 + The proportion of BMDMs was the lowest (about 25%), indicating that ICG & lipoic acid@ferritin & albumin nanoparticles can effectively promote the polarization of M2-BMDMs to M1 type.

[0068] Example 5

[0069] In vivo tumor inhibition effect study:

[0070] Experimental method: According to 1×10 6 Mouse breast tumor cells 4T1 were subcutaneously inoculated into the right side of the back of female Balb / c mice at an inoculation density of 10 cells / mouse. When the tumor reached 50 mm 3 The mice were randomly divided into 4 groups (n=5), namely, saline group, free indocyanine green group, indocyanine green nanoparticle group, indocyanine green@ferritin & albumin nanoparticle group and indocyanine green & lipoic acid@ferritin & albumin nanoparticle group (indocyanine green: 5 mg / kg, administered by tail vein injection). The drug was administered once a day for three days. Twelve hours after administration, the tumor site of the mice in the laser group was irradiated with 0.5W / cm 2 , 1.5 min of laser irradiation, and the tumor volume of each group of experimental mice was measured every two days; when the tumor volume of the mice in the normal saline group reached ~2000mm 3 The experiment was terminated when . The excised tumor tissue was weighed. Another tumor tissue was ground, sieved, and red blood cells were removed by red blood cell lysis solution. It was stained with different fluorescent-labeled antibodies and detected by flow cytometry. The measurement results were as follows: Figure 5-Figure 7 shown.

[0071] Depend on Figure 5 It can be seen that compared with the saline group, the free indocyanine green group, the indocyanine green nanoparticle group, the indocyanine green@ferritin & albumin nanoparticle group and the indocyanine green & lipoic acid@ferritin & albumin nanoparticle group can inhibit tumor growth; among them, the indocyanine green & lipoic acid@ferritin & albumin nanoparticle group has the lowest average tumor weight. It can be seen that the indocyanine green & lipoic acid@ferritin & albumin nanoparticles of the present invention have a better synergistic effect under the action of laser and can better inhibit tumor growth.

[0072] Depend on Figure 6Compared with the saline group, the free indocyanine green group, the indocyanine green nanoparticle group, the indocyanine green@ferritin & albumin nanoparticle group and the indocyanine green & lipoic acid@ferritin & albumin nanoparticle group, the CD11C + CD86 + The proportion of DCs increased significantly in the indocyanine green & lipoic acid @ ferritin & albumin nanoparticles group. + CD86 + The proportion of DCs is the highest. It can be seen that the indocyanine green & lipoic acid @ ferritin & albumin nanoparticles of the present invention have a better synergistic effect under the action of laser, which can significantly promote the maturation and activation of DCs in tumor tissues, initiate anti-tumor immune response, and produce the best therapeutic effect.

[0073] Depend on Figure 7 Compared with the saline group, the free indocyanine green group, the indocyanine green nanoparticle group, the indocyanine green@ferritin & albumin nanoparticle group and the indocyanine green & lipoic acid@ferritin & albumin nanoparticle group, the F4 / 80 + CD206 + The proportion of TAMs in the tumor tissue of the indocyanine green & lipoic acid @ ferritin & albumin nanoparticles group was significantly reduced. + CD206 + The proportion of TAMs is the lowest. It can be seen that the indocyanine green & lipoic acid @ ferritin & albumin nanoparticles of the present invention have a better synergistic effect under the action of laser, which can significantly reduce the proportion of M2-TAMs in tumor tissue, regulate the tumor immunosuppressive microenvironment, and inhibit tumor growth.

[0074] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A method for preparing tumor immune microenvironment-regulated light-activated ferroptosis nanoparticles, characterized in that: The following steps are involved: Albumin and ferritin are dissolved in water, and the pH is adjusted to alkaline before adding a photosensitizer and lipoic acid, and then a solvent is added after mixing to carry out a mixing reaction, and then a cross-linking agent is added. After continuing the reaction, the reaction is centrifuged and dried to obtain the tumor immune microenvironment regulating light-activated ferroptosis nanoparticles.

2. The preparation method according to claim 1, characterized in that: The photosensitizer is indocyanine green or neoindocyanine green; and / or The cross-linking agent is glutaraldehyde.

3. The preparation method according to claim 1, characterized in that: The mass ratio of the albumin, the ferritin, the lipoic acid and the photosensitizer is 15:5:2.5:0.

5.

4. The preparation method according to claim 1, characterized in that: The solvent is anhydrous ethanol.

5. The preparation method according to claim 1, characterized in that: The said adjusting the pH to be alkaline means adjusting the pH to 9.

0.

6. A tumor immune microenvironment-regulated light-activated ferroptosis nanoparticle prepared according to the preparation method according to any one of claims 1 to 5.

7. Use of the tumor immune microenvironment regulating light-activated ferroptosis nanoparticles as claimed in claim 6 in the preparation of tumor immunotherapy drugs.

8. The use according to claim 7, characterized in that: The drug reverses the tumor immunosuppressive microenvironment by inducing ferroptosis of tumor cells, activating dendritic cells, and regulating the M1 polarization of M2 tumor-associated macrophages.

9. A tumor immunotherapy drug, characterized in that: The active ingredient includes the tumor immune microenvironment regulating light-activated ferroptosis nanoparticles as described in claim 6.

10. The tumor immunotherapy drug according to claim 9, characterized in that: The tumor immunotherapy drug also includes pharmaceutically acceptable excipients.

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