Covalent bonding between lanthanide ions dramatically enhances exchange interactions between their magnetic moments and leads to fascinating magnetic properties. Particularly attractive for this goal are single-electron lanthanide-lanthanide bonds, which were first realized in metal dimers encapsulated in endohedral metallofullerenes. So far, stabilization of the single-electron bond in fullerenes required modification of the carbon cage by replacing one carbon with nitrogen or by an exohedral attachment of a radical group, which inevitably perturbed the cage symmetry and thereby affected the magnetic anisotropy. Here, we report on the isolation of [M2@I h-C80]- anions (M = Tb, Dy) with single-electron M-M bonds, for which we developed a chromatography-free separation protocol. Thorough investigation of their dynamic magnetic properties and relaxation mechanisms in comparison to those of M2@C80(CF3), M2@C80(CH2Ph), and M2@C79N showed that highly symmetric [M2@C80]- anions exhibit the highest blocking temperatures in the series. Magnetization relaxation parameters depend considerably on the mode of the cage functionalization, and Dy2 is more susceptible to the variation of its environment than Tb2. Our work opens the way to capture elusive anions of endohedral metallofullerenes without perturbing their cage symmetry, facilitating deep investigation of these fascinating molecules.

Glioblastoma (GBM) presents a significant challenge because of its immunosuppressive microenvironment. The standard treatment protocol, including surgery, radiotherapy, and temozolomide, has been unable to alleviate immunosuppression. Doxorubicin chemotherapy induces immunogenic cell death in cancer cells, reshaping an immune-activated microenvironment. Here, we investigated the mechanism of immune activation induced by doxorubicin in tumor-associated macrophages (TAMs). Radiotherapy and temozolomide plus doxorubicin inhibited tumor growth and reduced the levels of immunosuppressive markers. Mechanically, doxorubicin promotes the production of lactate through activating lactate dehydrogenase A (LDHA) to upregulate the transcription of inflammatory cytokines. Our study confirmed a new mechanism by which doxorubicin remodels the tumor microenvironment by promoting the glycolytic process and lactic acid production, suggesting that combining radiotherapy and temozolomide with doxorubicin chemotherapy may be a potential strategy for GBM treatment.

Metallofullerenes with endohedral lanthanides have emerged as a versatile class of single-molecule magnets owing to strong single-ion magnetic anisotropy, which can be realized in the interior of the fullerene cage. Since exohedral chemical modification of fullerenes is often used to adjust their properties and processability for prospective practical applications, it is necessary to understand how it can affect their magnetic properties. In this work, we studied how a popular [2 + 1] cycloaddition reaction, photochemical addition of adamantylidene (Ad), affects single-ion magnetic anisotropy and single-molecule magnetism of MSc2N@C80 (M = Nd, Dy). For each lanthanide, the reaction yielded [5,6]-open and [6,6]-open isomers of the monoadduct MSc2N@C80(Ad). Paramagnetic 1H NMR was demonstrated that the Ad-addition site in [5,6] isomers is predominantly coordinated by Sc, whereas both Sc and lanthanide coordination coexist in [6,6] isomers. Ab initio calculations and Nd-based photoluminescence showed that the [5,6] isomer has enhanced ligand-field splitting, whereas coordination of the lanthanide to the Ad-addition site in the [6,6] isomer reduces magnetic axiality and ligand-field splitting. For DySc2N@C80(Ad), Dy-Ad coordination leads to a noticeable reduction in the blocking temperature of magnetization, whereas Dy coordination to the unfunctionalized fragments of the fullerene cage improves the SMM performance in comparison to the unfunctionalized DySc2N@C80. Thus, carbene addition can enhance or deteriorate SMM properties depending on the regioisomerism and the lanthanide-cage coordination geometry in MSc2N@C80(Ad) adducts. These results demonstrate that chemical derivatization of EMFs can become a useful tool for improving their magnetic properties, but will require careful evaluation of different factors for each reaction type.

The poor prognosis of glioblastoma (GBM) is partly attributed to the immunosuppressive microenvironment. The combination of standard temozolomide and other chemotherapy drugs can significantly enhance the therapeutic effect by reshaping the immune microenvironment. Cisplatin treatment induces immunogenic cell death in tumor cells, stimulating an immune response. Here, we investigated the immune-activating effect of cisplatin on tumor-associated macrophages (TAMs). The therapeutic benefit of temozolomide plus cisplatin was showed in a murine model of GBM, accompanied by the inhibition of tumor growth and enhancement of pro-inflammatory activation of TAMs. Furthermore, cisplatin treatment downregulated the expression of CD47 in glioma stem cells, SIRPα, and IL-6 in TAMs, thus promoting M1-like polarization of TAMs to enhance an immune-activating tumor microenvironment. Mechanically, cisplatin decreases the production of lactic acid by downregulating LDHA expression. A low level of lactate reduces histone H3K18 lactylation on the CD47 and IL-6 promoters, thereby suppressing gene transcription. Our study reveals a new mechanism by which cisplatin remodels the immune tumor microenvironment, suggesting that combining temozolomide with cisplatin chemotherapy may be a new treatment option for GBM.

PURPOSE:Prohibitin2 (PHB2), located in inner mitochondrial membrane (IMM), is an important receptor to induce mitophagy. PHB2 was identified as a cancer-promoting factor in most cancers. However, the function of PHB2 in glioma cells remains unclear. This study delved into the impact of PHB2 knockdown on the phenotype, radiosensitivity and mitophagy of glioma cells. METHODS:PHB2 expression and its clinical relevance in glioma were investigated by western blot, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and TCGA databases. The malignant phenotypes of glioma cells were analyzed in vitro using cell proliferation, cell cycle, wound healing and transwell assay. The radiosensitivity of glioma cells was detected by colony forming assay. The potential mechanism by which PHB2 regulated mitophagy was investigated by coimmunoprecipitation assay. RESULTS:The expression of PHB2 was significantly upregulated in glioma cells and closely correlated with the malignant degree of glioma. The knockdown of PHB2 inhibited the proliferation, migration and invasion activities of glioma cells. Furthermore, PHB2 knockdown enhanced the radiosensitivity of normoxic and hypoxic glioma cells and suppressed the ionizing radiation-induced mitophagy in glioma cells. Cyanide 3-chlorophenylhydrazone (CCCP), a mitophagy agonist, could reverse the phenotypes and radiosensitivity changes elicited by PHB2 knockdown. Additionally, PHB2 regulated the expression of PGAM5 and PINK1 by directly binding to PARL. CONCLUSIONS:Our findings revealed that PHB2 knockdown decreased glioma malignant phenotypes and radio-resistance by inhibiting mitophagy via PARL-PGAM5-PINK1-Parkin pathway. PHB2 is a promising candidate target for the development of new therapeutic strategy to enhance the efficacy of radiotherapy for glioma.

A pyramidal Nd 2 ScN cluster was trapped in a C 80 fullerene cage. The precise structure was unambiguously elucidated by single crystal X-ray diffraction with four sites of the light N atom.

Magnetic properties of lanthanide endohedral metallofullerenes are strongly modulated by intramolecular metal-metal interactions, which suppress the quantum tunneling of magnetization (QTM) in Dy2ScN@C80, but lead to magnetic frustration with pronounced QTM in Dy3N@C80. In this work, we explore how exohedral chemical modification of Dy2ScN@C80 and Dy3N@C80 by photochemical addition of adamantylidene (Ad) affects Dy···Dy interactions and influences their single-molecule magnetism. For each fullerene, the photochemical reaction with adamantane aziridine produced two isomers of Ad monoadduct, minor [5,6]-open and major [6,6]-open. By virtue of the high sensitivity of the 1H nuclear spin probe in the Ad moiety to the position of Dy ions, paramagnetic NMR helped to establish Sc-Ad coordination in the [5,6] isomer and predominant Dy-Ad coordination in the [6,6] isomer of Dy2ScN@C80(Ad). SQUID magnetometry and relaxation measurements demonstrated that Ad addition has almost no effect on the strength of the Dy···Dy coupling in the [6,6] isomer of Dy2ScN@C80(Ad), but it does increase the coupling in the [5,6] counterpart by 20%. The blocking temperature of magnetization and the coercivity are both softened by adamantylidene addition, irrespective of the isomeric structure of Dy2ScN@C80(Ad). For Dy3N@C80(Ad), Ad addition substantially increased Dy···Dy coupling constants and the energy spread of exchange-coupled states in comparison to that of Dy3N@C80 and lifted geometric frustration. As a result, both Dy3N@C80(Ad) isomers exhibit open hysteresis without pronounced QTM signatures and have a higher blocking temperature of magnetization than the pristine Dy3N@C80. Our work demonstrates that chemical derivatization can have profound influence on the metal-metal coupling and relaxation of magnetization in metallofullerene molecular magnets.

Our knowledge about endohedral metallofullerenes (EMFs) is restricted to the structures with sufficient kinetic stability to be extracted from the arc-discharge soot and processed by chromatographic and structural techniques. For the most abundant rare-earth monometallofullerene MIII@C82, experimental studies repeatedly demonstrated C2v(9) and Cs(6) carbon cage isomers, while computations predicted equal stability of the "missing" C3v(8) isomer. Here we report that this isomer is indeed formed but has not been recovered from soot using standard protocols. Using a combination of redox extraction and subsequent benzylation and trifluoromethylation with single-crystal XRD analysis of CF3 adduct, we prove that Dy@C3v(8)-C82 is one of the most abundantly produced metallofullerenes, which was not identified in earlier studies because of the low kinetic stability. Further, using the Dy@C3v(8)-C82(CF3) and Dy@C3v(8)-C82(CH2Ph) monoadducts for the case study, we analyzed the role of metal-fullerene bonding on the single-ion magnetic anisotropy of Dy in EMFs. The multitechnique approach, combining ab initio calculations, EPR spectroscopy, and SQUID magnetometry, demonstrated that coordination of the Dy ion to the fullerene cage induces moderate, nonaxial, and very fluid magnetic anisotropy, which strongly varies with small alterations in the Dy-fullerene coordination geometry. As a result, Dy@C3v(8)-C82(CH2Ph) is a weak field-induced single-molecule magnet (SMM), whose signatures of magnetic relaxation are detectable only below 3 K. Our results demonstrate that metal-cage interactions should have a detrimental effect on the SMM performance of EMFs. At the same time, the strong variability of the magnetic anisotropy with metal position suggests tunability and offers strategies for future progress.

Nd-based nitride clusterfullerenes NdM2N@C80 with rare-earth metals of different sizes (M = Sc, Y, Lu) were synthesized to elucidate the influence of the cluster composition, shape and internal strain on the structural and magnetic properties. Single crystal X-ray diffraction revealed a very short Nd-N bond length in NdSc2N@C80. For Lu and Y analogs, the further shortening of the Nd-N bond and pyramidalization of the NdM2N cluster are predicted by DFT calculations as a result of the increased cluster size and a strain caused by the limited size of the fullerene cage. The short distance between Nd and nitride ions leads to a very large ligand-field splitting of Nd3+ of 1100-1200 cm-1, while the variation of the NdM2N cluster composition and concomitant internal strain results in the noticeable modulation of the splitting, which could be directly assessed from the well-resolved fine structure in the Nd-based photoluminescence spectra of NdM2N@C80 clusterfullerenes. Photoluminescence measurements also revealed an unprecedentedly strong nephelauxetic effect, pointing to a high degree of covalency. The latter appears detrimental to the magnetic axiality despite the strong ligand field. As a result, the ground magnetic state has considerable transversal components of the pseudospin g-tensor, and the slow magnetic relaxation of NdSc2N@C80 could be observed by AC magnetometry only in the presence of a magnetic field. A combination of the well-resolved magneto-optical states and slow relaxation of magnetization suggests that Nd clusterfullerenes can be useful building blocks for magneto-photonic quantum technologies.

Radiotherapy alters the tumor microenvironment and reprograms cellular metabolism. Transition of tumor cell phenotypes contributes to post-radiotherapy tumor recurrence. Low radiosensitivity of glioma stem cells is one of the reasons for radiotherapy failure. Here, we found that radiotherapy resulted in a higher proportion of infiltration of inflammatory macrophages in glioma non-stem cell grafts compared with that in glioma stem cell-transplanted tumors in a mouse model, where immunosuppressive macrophages dominated in the tumor microenvironment. In radioresistant glioma stem cells, ionizing radiation upregulated CD47 expression by AMP-activated protein kinase (AMPK), resulting in the inhibition of phagocytosis and the promotion of M2-like polarization in macrophages. Ionizing radiation promoted H3K4 methylation on CD47 promotor by downregulating KDM5A. Hyper-phosphorylated retinoblastoma protein RB maintained its dissociation status with KDM5A following AMPK activation, which inhibited the demethylated function of KDM5A. In contrast, in radiosensitive glioma non-stem cells, RB S807/S811 hypo-phosphorylation contributed to the binding of RB with KDM5A, which suppressed H3K4 methylation on CD47 promotor. In addition, ionizing radiation promoted H3K27 acetylation on CD47 promotor by HDAC7 in glioma stem cells. These data suggested that glioma stem cells reprogrammed the tumor immune microenvironment by epigenetic editing to escape macrophage phagocytosis after ionizing radiation. Targeting CD47 might be a potential strategy to sensitize glioblastoma to radiotherapy.

BACKGROUND:Glioma stem cells (GSCs), which are known for their therapy resistance, play a substantial role in treatment inefficacy for glioblastoma multiforme (GBM). TRIM37, a member of the tripartite motif (TRIM) protein family initially linked to a rare growth disorder, has been recognized for its oncogenic role. However, the mechanism by which TRIM37 regulates tumor growth in glioma and GSCs is unclear. METHODS:For the in vitro experiments, gene expression was measured by western blotting, RT-qPCR, and immunofluorescence. Cell viability was detected by CCK-8, and cell apoptosis was detected by flow cytometry. The interaction between Enhancer of Zeste Homolog 2 (EZH2) and TRIM37 was verified by co-immunoprecipitation (Co-IP). The interaction between EZH2 and the PTCH1 promoter was verified using dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP). For the in vivo experiments, an orthotopically implanted glioma mouse model was used to validate tumor growth. RESULTS:The expression of TRIM37 is higher in GSCs compared with matched non-GSCs. TRIM37 knockdown promotes apoptosis, decreased stemness in GSCs, and reduces tumor growth in GSCs xenografts of nude mice. TRIM37 and EZH2 co-localize in the nucleus and interact with each other. TRIM37 knockdown or EZH2 inhibition downregulates the protein expressions associated with the Sonic Hedgehog (SHH) pathway. EZH2 epigenetically downregulates PTCH1 to activate SHH pathway in GSCs. CONCLUSIONS:TRIM37 maintains the cell growth and stemness in GSCs through the interaction with EZH2. EZH2 activates SHH stem cell signaling pathway by downregulating the expression of SHH pathway suppressor PTCH1. Our findings suggest that TRIM37 may be a potential therapeutic target for GBM.

PURPOSE:A strong immunosuppressive tumor microenvironment (TME) represents the major barrier responsible for the failure of current immunotherapy approaches in treating Glioblastoma Multiforme (GBM). Within the TME, the regulatory T cells (Tregs) exert immunosuppressive effects on CD8+ T cell - mediated anti-cancer immune killing. Consequently, targeting and inhibiting their immunosuppressive function emerges as an effective therapeutic strategy for GBM. The present study aimed to investigate the mechanisms and effects of Suberanilohydroxamic Acid (SAHA), a histone deacetylase inhibitor, on immunosuppressive Tregs.METHODS:The tumor-infiltrating immune cells in the immunocompetent GBM intracranial implanted xenograft mouse model were analyzed by immunohistochemistry and flow cytometry techniques. The mRNA expressions were assessed through the RT-qPCR method, while the related protein expressions were determined using western blot, ELISA, immunofluorescence (IF), and flow cytometry techniques. The relationship between c-Myc and C-C motif Chemokine Ligand 1 (CCL1) promotor was validated through a dual-luciferase reporter assay system and chromatin immunoprecipitation.RESULTS:SAHA suppressed effectively tumor growth and extended significantly overall survival in the immunocompetent GBM intracranial xenograft mouse model. Additionally, it promoted the infiltration of CD8+ T lymphocytes while suppressed the infiltration of CD4+ CD25+ Tregs. Furthermore, SAHA enhanced anti-PD-L1 immune therapy in the intracranial xenograft of mice. Mechanistically, SAHA exerted its effects by inhibiting histone deacetylase 2 (HDAC2), thereby suppressing the binding between c-Myc and the CCL1 promotor.CONCLUSION:SAHA inhibited the binding of c-Myc with the CCL1 promoter and then suppressed the transcription of CCL1.Additionally, it effectively blocked the interplay of CCL1-CCR8, resulting in reduced activity of Tregs and alleviation of tumor immunosuppression.

Hypoxia can weaken the efficacy of radiotherapy and decrease tumor immunogenicity leading to immune escape. Thus, a thorough understanding of the key signaling pathways regulated by hypoxia is vitally important to enhance the radiosensitivity and improve immunosuppressive microenvironment of glioma. In this study, we verified the crucial role of hypoxia-inducible gene 2 (HIG-2) in lipid droplet (LD) accumulation and demonstrated that HIG-2 binding to frizzled class receptor 10 (FZD10) activated Wnt/β-catenin signaling pathway and increased its downstream insulin-like growth factor binding protein 2 (IGFBP2) level in microparticles (MPs) derived from glioma stem cells (GSCs), leading to decreased radiosensitivity and immunogenicity of MPs-receiving cells via the cross-talk between GSCs and non-stem glioma cells (GCs). These findings suggest that HIG-2 may be a promising target in glioma radiotherapy and/or immunotherapy.

医学免疫学作为一门联系基础医学与临床医学的重要学科,依照"两性一度"标准,如何推进医学免疫学课程建设的改革,是影响医学生培养质量的重要环节之一.传统教学方式的学生往往处于被动接受知识状态,因此不能充分发挥其主动性,学生学习热情不高,严重影响教学效果,很难保证现代大学教育"两性一度"的建设标准.因此需改变教学方式,调动学生学习积极性.本研究尝试将对分课堂与情境教学法相结合,通过创设免疫学相关的情境问题,利用对分课堂充分讨论与自主学习,推动具有"两性一度"的高质量医学免疫学课程建设.

免疫学作为现代生命科学的前沿学科之一,是基础医学与临床医学硕士、博士培养的重要基础课程.同时,科研仪器操作技术是衔接免疫学理论与免疫学实验操作的关键纽带.因此,本教学团队以免疫科研为主线,以讲解相关仪器为教学策略,从明确课程目标、整合学科知识、设计课程考核和评价等方面充分挖掘思政元素,将课程与科研实践密切连接.结果表明,课程思政元素的融入不仅能实现教学方法的不断优化,还能培养学生精益求精、追求卓越的工匠精神,以及敬佑生命、甘于奉献的医者精神,从而更好地贯彻落实立德树人的根本任务.

Under background of new medical science,how to train high-quality medical talents with post competence is one of important contents of medical higher education.In order to train professional medical talents in different fields,make them more suitable for characteristics of their majors,and adapt to needs of future career development,"precision teaching"should be carried out in teaching,including precision of course content design,teaching mode and assessment method,so as to achieve goal of cultivating professional medical talents with precision.Therefore,guided by competency of new medical posts,our teaching team try to explore precision teaching in course construction of Medical Immunology.Here we introduce specific method by taking chapter of Antibody as an example.

PurposeAfter irradiation, double-stranded DNA leaked into the cytoplasm activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, leading to the production of type I interferon (IFNI). In this study, we sought to probe the effect of ionizing radiation on activity of cGAS-STING-IFNI pathway in normoxic or hypoxic glioma cells and explore a more effective method to activate the signaling pathway, thereby activating the anti-tumor immune response and improving the therapeutic effect of radiotherapy for glioma.Materials and methodsHuman glioma cells U251 and T98G cultured in normoxia or hypoxia (1% O-2) were irradiated with different doses of X-ray. The relative expressions of cGAS, IFN-I stimulated genes (ISGs), and three-prime repair exonuclease 1 (TREX1) were detected by qPCR. The expression levels of interferon regulatory factor 3 (IRF3) and p-IRF3 proteins were detected by Western blot. The production of cGAMP and IFN-& beta; in the supernatant was detected by ELISA assay. U251 and T98G cell lines with stable knockdown of TREX1 were established after transfection with lentivirus vectors. EdU cell proliferation assay was used to screen suitable metal ions concentrations. The phagocytosis of DCs was observed by immunofluorescence microscope. The phenotype of DCs was detected by flow cytometry. The migration ability of DCs was detected by a transwell experiment.ResultsWe found that cytosolic dsDNA, 2 & PRIME;3 & PRIME;-cGAMP, cGAS and ISGs expression, and IFN-& beta; in cell supernatant were all increased with the doses of X-ray in the range of 0-16 Gy in normoxic glioma cells. Nevertheless, hypoxia significantly inhibited the radiation-induced dose-dependent activation of cGAS-STING-IFNI pathway. Furthermore, manganese (II) ion (Mn2+) significantly improved cGAS-STING-IFNI pathway activation induced by X-ray in both normoxic and hypoxic glioma cells, thereby promoting the maturation and migration of DCs.ConclusionsThe responses of cGAS-STING-IFNI pathway to ionizing radiation were mainly investigated under normoxic condition, but the experiments described here indicated that hypoxia could hinder the pathway activation. However, Mn2+ showed radiosensitizing effects on the pathway under either normoxic or hypoxic conditions demonstrating its potential as a radiosensitizer for glioma through activating an anti-tumor immune response.

Abstract Aim Immunotherapy for glioblastoma multiforme (GBM) is limited because of a strongly immunosuppressive tumor microenvironment (TME). Remodeling the immune TME is an effective strategy to eliminate GBM immunotherapy resistance. Glioma stem cells (GSCs) are inherently resistant to chemotherapy and radiotherapy and involved in immune evasion mechanism. This study aimed to investigate the effects of histone methyltransferases 2 (EHMT2 or G9a) on immunosuppressive TME and whether this effect was related to changes on cell stemness. Methods Tumor‐infiltrating immune cells were analyzed by flow cytometry and immunohistochemistry in orthotopic implanted glioma mice model. The gene expressions were measured by RT‐qPCR, western blot, immunofluorescence, and flow cytometry. Cell viability was detected by CCK‐8, and cell apoptosis and cytotoxicity were detected by flow cytometry. The interaction of G9a and F‐box and WD repeat domain containing 7 (Fbxw7) promotor was verified by dual‐luciferase reporter assay and chromatin immunoprecipitation. Results Downregulation of G9a retarded tumor growth and extended survival in an immunocompetent glioma mouse model, promoted the filtration of IFN‐γ + CD4+ and CD8+ T lymphocytes, and suppressed the filtration of PD‐1+ CD4+ and CD8+ T lymphocytes, myeloid‐derived suppressor cells (MDSCs) and M2‐like macrophages in TME. G9a inhibition decreased PD‐L1 and increased MHC‐I expressions by inactivating Notch pathway companying stemness decrease in GSCs. Mechanistically, G9a bound to Fbxw7, a Notch suppressor, to inhibit gene transcription through H3K9me2 of Fbxw7 promotor. Conclusion G9a promotes stemness characteristics through binding Fbxw7 promotor to inhibit Fbxw7 transcription in GSCs, forming an immunosuppressive TME, which provides novel treatment strategies for targeting GSCs in antitumor immunotherapy.

目的：探究蛋氨酸缺失对GBM放射敏感性以及辐射诱导ICD的影响和机制，方法：Edu实验检测GBM增殖情况，免疫荧光实验检测DNA损伤情况，克隆实验检测细胞克隆存活率，电镜实验检测自噬体形成以及线粒体自噬，流式细胞术检测细胞凋亡、CRT表面暴露。生物发光实验检测上清中ATP含量，Western blot检测自噬相关蛋白LC3B、P62表达水平以及ER应激通路相关蛋白PERK、IRE1α的磷酸化水平。结果：常氧或乏氧条件下，蛋氨酸缺失抑制GBM细胞增殖、促进细胞凋亡，增加了GBM的放射敏感性，蛋氨酸缺失促进自噬体形成以及增加线粒体自噬，上调L3II表达、下调P62表达，联合3-MA进一步促进GBM凋亡以及对GBM的放射敏感性更加显著，蛋氨酸缺失增强辐射诱导免疫原性细胞死亡，增强内质网应激相关通路PERK、IRE1α的磷酸化水平。结论：蛋氨酸缺失促进常氧或乏氧GBM的放射敏感性，其机理可能与其抑制GBM增殖、促进细胞凋亡，诱导GBM自噬相关。蛋氨酸缺失通过内质网应激相关通路PERK、IER1α的磷酸化增强IR对GBM的免疫原性细胞死亡。