Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer

Abstract

Loss or downregulation of major histocompatibility complex (MHC) molecules represents a key mechanism by which tumours escape immune recognition and acquire resistance to immunotherapeutic interventions. This review focuses on the central regulatory pathways. These includes transcriptional repression, lysosomal degradation, and post-translational modifications that disrupt MHC stability, trafficking, and surface expression. We highlight how these mechanisms impair antigen presentation and contribute to tumour immune evasion. In addition, we explore emerging therapeutic strategies focused on reactivating MHC expression to enhance tumour immunogenicity and improve the efficacy of immunotherapy. Finally, we discuss the translational potential of these approaches and the remaining challenges, including tumour heterogeneity, immunotoxicity and dynamic regulation within the tumour microenvironment, that must be addressed to optimize MHC-targeted interventions in cancer immunotherapy.

Keywords

cancer immunotherapy / immune responses / MHC loss / tumour microenvironment

References

[1] Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024; 74: 12-49.

[2] Yu X, Zhai X, Wu J, et al. Evolving perspectives regarding the role of the PD-1/PD-L1 pathway in gastric cancer immunotherapy. Biochim Biophys Acta Mol Basis Dis. 2024; 1870: 166881.

[3] Splendiani E, Besharat ZM, Covre A, Maio M, Di Giacomo AM, Ferretti E. Immunotherapy in melanoma: can we predict response to treatment with circulating biomarkers?. Pharmacol Ther. 2024; 256: 108613.

[4] Ramapriyan R, Vykunta VS, Vandecandelaere G, et al. Altered cancer metabolism and implications for next-generation CAR T-cell therapies. Pharmacol Ther. 2024; 259: 108667.

[5] Niu L, Wang Q, Feng F, et al. Small extracellular vesicles-mediated cellular interactions between tumor cells and tumor-associated macrophages: implication for immunotherapy. Biochim Biophys Acta Mol Basis Dis. 2024; 1870: 166917.

[6] Sonkin D, Thomas A, Teicher BA. Cancer treatments: past, present, and future. Cancer Genet. 2024; 286-287: 18-24.

[7] Joshi RM, Telang B, Soni G, Khalife A. Overview of perspectives on cancer, newer therapies, and future directions. Oncol Transl Med. 2024; 10: 105-109.

[8] Neefjes J, Jongsma ML, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. 2011; 11: 823-836.

[9] Rock KL, Reits E, Neefjes J. Present yourself! by MHC Class I and MHC Class II molecules. Trends Immunol. 2016; 37: 724-737.

[10] Pishesha N, Harmand TJ, Ploegh HL. A guide to antigen processing and presentation. Nat Rev Immunol. 2022; 22: 751-764.

[11] Hulpke S, Tampe R. The MHC I loading complex: a multitasking machinery in adaptive immunity. Trends Biochem Sci. 2013; 38: 412-420.

[12] Roche PA, Furuta K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol. 2015; 15: 203-216.

[13] Wieczorek M, Abualrous ET, Sticht J, et al. Major histocompatibility complex (MHC) class I and MHC class II proteins: conformational plasticity in antigen presentation. Front Immunol. 2017; 8: 292.

[14] Trowsdale J, Knight JC. Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet. 2013; 14: 301-323.

[15] Garrido F, Romero I, Aptsiauri N, Garcia-Lora AM. Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype. Int J Cancer. 2016; 138: 271-280.

[16] Parham P, Ohta T. Population biology of antigen presentation by MHC class I molecules. Science. 1996; 272: 67-74.

[17] Zhang Y, Chen Y, Li Y, et al. The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Iota. Proc Natl Acad Sci U S A. 2021; 118: e2024202118.

[18] Whiteside TL. Immune responses to malignancies. J Allergy Clin Immunol. 2010; 125: S272-283.

[19] Rossjohn J, Gras S, Miles JJ, Turner SJ, Godfrey DI, McCluskey J. T cell antigen receptor recognition of antigen-presenting molecules. Annu Rev Immunol. 2015; 33: 169-200.

[20] Dennison TW, Edgar RD, Payne F, et al. Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's disease. Gut. 2024; 73: 1464-1477.

[21] Cui D, Wang J, Zeng Y, et al. Generating hESCs with reduced immunogenicity by disrupting TAP1 or TAPBP. Biosci Biotechnol Biochem. 2016; 80: 1484-1491.

[22] Ishina IA, Zakharova MY, Kurbatskaia IN, Mamedov AE, Belogurov AA, Gabibov AG. MHC class II presentation in autoimmunity. Cells. 2023; 12: 314.

[23] Zavidij O, Haradhvala NJ, Mouhieddine TH, et al. Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma. Nat Cancer. 2020; 1: 493-506.

[24] Christopher MJ, Petti AA, Rettig MP, et al. Immune escape of relapsed AML cells after allogeneic transplantation. N Engl J Med. 2018; 379: 2330-2341.

[25] Dhatchinamoorthy K, Colbert JD, Rock KL. Cancer immune evasion through loss of MHC class I antigen presentation. Front Immunol. 2021; 12: 636568.

[26] Luo X, Qiu Y, Fitzsimonds ZR, Wang Q, Chen Q, Lei YL. Immune escape of head and neck cancer mediated by the impaired MHC-I antigen presentation pathway. Oncogene. 2024; 43: 388-394.

[27] Rodig SJ, Gusenleitner D, Jackson DG, et al. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci Transl Med. 2018; 10.

[28] Taylor BC, Balko JM. Mechanisms of MHC-I downregulation and role in immunotherapy response. Front Immunol. 2022; 13: 844866.

[29] Shklovskaya E, Rizos H. MHC Class I deficiency in solid tumors and therapeutic strategies to overcome it. Int J Mol Sci. 2021; 22.

[30] Fang Y, Wang L, Wan C, et al. MAL2 drives immune evasion in breast cancer by suppressing tumor antigen presentation. J Clin Invest. 2021; 131.

[31] Deng Y, Xia X, Zhao Y, et al. Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance. Nat Commun. 2021; 12: 7041.

[32] Wang H, Liu B, Wei J. Beta2-microglobulin(B2M) in cancer immunotherapies: biological function, resistance and remedy. Cancer Lett. 2021; 517: 96-104.

[33] Wright KL, Ting JP. Epigenetic regulation of MHC-II and CIITA genes. Trends Immunol. 2006; 27: 405-412.

[34] Tovar Perez JE, Zhang S, Hodgeman W, et al. Epigenetic regulation of major histocompatibility complexes in gastrointestinal malignancies and the potential for clinical interception. Clin Epigenetics. 2024; 16: 83.

[35] Majumder P, Lee JT, Rahmberg AR, et al. A super enhancer controls expression and chromatin architecture within the MHC class II locus. J Exp Med. 2020; 217.

[36] Lee JH, Shklovskaya E, Lim SY, et al. Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition. Nat Commun. 2020; 11: 1897.

[37] Xu HG, Chen C, Chen LY, Pan S. Pan-cancer analysis identifies the IRF family as a biomarker for survival prognosis and immunotherapy. J Cell Mol Med. 2024; 28: e18084.

[38] Zhang D, Zhan D, Zhang R, et al. Treg-derived TGF-beta1 dampens cGAS-STING signaling to downregulate the expression of class I MHC complex in multiple myeloma. Sci Rep. 2024; 14: 11593.

[39] Qiong L, Shuyao X, Shan X, et al. Recent advances in the glycolytic processes linked to tumor metastasis. Curr Mol Pharmacol. 2024; 17: e18761429308361.

[40] Xie J, Liu M, Deng X, et al. Gut microbiota reshapes cancer immunotherapy efficacy: mechanisms and therapeutic strategies. Imeta. 2024; 3: e156.

[41] Yin CL, Ma YJ. The regulatory mechanism of hypoxia-inducible factor 1 and its clinical significance. Curr Mol Pharmacol. 2024; 17: e18761429266116.

[42] Yang Q, Lv Z, Wang M, et al. LATS1/2 loss promote tumor immune evasion in endometrial cancer through downregulating MHC-I expression. J Exp Clin Cancer Res. 2024; 43: 54.

[43] Wang B, Jiang B, Du L, et al. Tumor-intrinsic RGS1 potentiates checkpoint blockade response via ATF3-IFNGR1 axis. Oncoimmunology. 2023; 12: 2279800.

[44] Xiong W, Chen Y, Zhang C, et al. Pharmacologic inhibition of IL11/STAT3 signaling increases MHC-I expression and T cell infiltration. J Transl Med. 2023; 21: 416.

[45] Djajawi TM, Pijpers L, Srivaths A, et al. PRMT1 acts as a suppressor of MHC-I and anti-tumor immunity. Cell Rep. 2024; 43: 113831.

[46] Sun J, Wang P, Yi Z, et al. Blocking WNT7A enhances MHC-I antigen presentation and enhances the effectiveness of immune checkpoint blockade therapy. Cancer Immunol Res. 2024; 13(3): 400-416.

[47] Gu SS, Zhang W, Wang X, et al. Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade. Cancer Discov. 2021; 11: 1524-1541.

[48] Sari G, Dhatchinamoorthy K, Orellano-Ariza L, Ferreira LM, Brehm MA, Rock K. IRF2 loss is associated with reduced MHC I pathway transcripts in subsets of most human cancers and causes resistance to checkpoint immunotherapy in human and mouse melanomas. J Exp Clin Cancer Res. 2024; 43: 276.

[49] Wang X, Chai Y, Quan Y. NPM1 inhibits tumoral antigen presentation to promote immune evasion and tumor progression. J Hematol Oncol. 2024; 17: 97.

[50] Li X, Yi H, Jin Z. MCRS1 sensitizes T cell-dependent immunotherapy by augmenting MHC-I expression in solid tumors. J Exp Med. 2024; 221: e20240959.

[51] Burr ML, Sparbier CE, Chan KL, et al. An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell. 2019; 36: 385-401 e388.

[52] Lehmann BD, Colaprico A, Silva TC, et al. Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes. Nat Commun. 2021; 12: 6276.

[53] Wijdeven RH, Luk SJ, Schoufour TAW, et al. Balanced epigenetic regulation of MHC class I expression in tumor cells by the histone ubiquitin modifiers BAP1 and PCGF1. J Immunol. 2024; 212: 446-454.

[54] Deng K, Liang L, Yang Y, et al. The Wdr5-H3K4me3 epigenetic axis regulates pancreatic tumor immunogenicity and immune suppression. Int J Mol Sci. 2024; 25.

[55] Zhang M, Wang G, Ma Z, et al. BET inhibition triggers antitumor immunity by enhancing MHC class I expression in head and neck squamous cell carcinoma. Mol Ther. 2022; 30: 3394-3413.

[56] Zheng J, Yang T, Gao S, et al. miR-148a-3p silences the CANX/MHC-I pathway and impairs CD8(+) T cell-mediated immune attack in colorectal cancer. FASEB J. 2021; 35: e21776.

[57] Luo H, Hu B, Gu XR, et al. The miR-23a/27a/24 - 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancer. Mol Cancer. 2024; 23: 285.

[58] Li G, Kryczek I, Nam J, et al. LIMIT is an immunogenic lncRNA in cancer immunity and immunotherapy. Nat Cell Biol. 2021; 23: 526-537.

[59] Yao H, Huang C, Zou J, et al. Extracellular vesicle-packaged lncRNA from cancer-associated fibroblasts promotes immune evasion by downregulating HLA-A in pancreatic cancer. J Extracell Vesicles. 2024; 13: e12484.

[60] Zhang Y, Li X, Zhang J, Liang H. Natural killer T cell cytotoxic activity in cervical cancer is facilitated by the LINC00240/microRNA-124-3p/STAT3/MICA axis. Cancer Lett. 2020; 474: 63-73.

[61] Yamamoto K, Venida A, Yano J, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020; 581: 100-105.

[62] Yamamoto K, Venida A, Perera RM, Kimmelman AC. Selective autophagy of MHC-I promotes immune evasion of pancreatic cancer. Autophagy. 2020; 16: 1524-1525.

[63] Sang W, Zhou Y, Chen H, et al. Receptor-interacting protein kinase 2 Is an immunotherapy target in pancreatic cancer. Cancer Discov. 2024; 14: 326-347.

[64] Zhang Z, Song B, Wei H, et al. NDRG1 overcomes resistance to immunotherapy of pancreatic ductal adenocarcinoma through inhibiting ATG9A-dependent degradation of MHC-1. Drug Resist Updat. 2024; 73: 101040.

[65] McBrearty N, Cho C, Chen J, et al. Tumor-Suppressive and immune-stimulating roles of cholesterol 25-hydroxylase in pancreatic cancer cells. Mol Cancer Res. 2023; 21: 228-239.

[66] Zhou X, Yang F, Huang L, et al. ITGB4/BNIP3 activates autophagy and reduces MHC-I expression to mediate tumour immune escape in pancreatic cancer cell lines. Immunology. 2025; 174: 264-277.

[67] Berquez M, Li AL, Luy MA, et al. A multi-subunit autophagic capture complex facilitates degradation of ER stalled MHC-I in pancreatic cancer. bioRxiv. 2024.

[68] Cheung PF, Yang J, Fang R, et al. Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression. Nat Commun. 2022; 13: 156.

[69] Liu Z, Li X, Muhammad A, et al. PACSIN1 promotes immunosuppression in gastric cancer by degrading MHC-I. Acta Biochim Biophys Sin (Shanghai). 2024; 56: 1473-1482.

[70] Herhaus L, Gestal-Mato U, Eapen VV, et al. IRGQ-mediated autophagy in MHC class I quality control promotes tumor immune evasion. Cell. 2024; 187: 7285-7302.e7229.

[71] Kong J, Xu S, Zhang P, Zhao Y. CXCL1 promotes immune escape in colorectal cancer by autophagy-mediated MHC-I degradation. Hum Immunol. 2023; 84: 110716.

[72] Zhang B, Li J, Hua Q, et al. Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation. J Immunother Cancer. 2023; 11: e005592.

[73] Lin W, Chen L, Zhang H, et al. Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation. Nat Commun. 2023; 14: 265.

[74] Qiao X, Cheng Z, Xue K, et al. Tumor-associated macrophage-derived exosomes LINC01592 induce the immune escape of esophageal cancer by decreasing MHC-I surface expression. J Exp Clin Cancer Res. 2023; 42: 289.

[75] Liao TT, Chen YH, Li ZY, et al. Hypoxia-induced long noncoding RNA HIF1A-AS2 regulates stability of MHC class I protein in head and neck cancer. Cancer Immunol Res. 2024; 12: 1468-1484.

[76] Li J, Wang K, Yang C, et al. Tumor-Associated macrophage-derived exosomal LINC01232 induces the immune escape in glioma by decreasing surface MHC-I expression. Adv Sci (Weinh). 2023; 10: e2207067.

[77] Chen X, Lu Q, Zhou H, et al. A membrane-associated MHC-I inhibitory axis for cancer immune evasion. Cell. 2023; 186: 3903-3920 e3921.

[78] Wang Z, Zhang L, Qiao A, Watson K, Zhang J, Fan GH. Activation of CXCR4 triggers ubiquitination and down-regulation of major histocompatibility complex class I (MHC-I) on epithelioid carcinoma HeLa cells. J Biol Chem. 2008; 283: 3951-3959.

[79] Tan L, Yin T, Xiang H, et al. Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response. Nat Commun. 2024; 15: 8569.

[80] Huang J, Tsang WY, Fang XN, et al. FASN inhibition decreases MHC-I degradation and synergizes with PD-L1 checkpoint blockade in hepatocellular carcinoma. Cancer Res. 2024; 84: 855-871.

[81] Torrejon DY, Galvez M, Abril-Rodriguez G, et al. Antitumor immune responses in B2M-Deficient Cancers. Cancer Immunol Res. 2023; 11: 1642-1655.

[82] Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in Melanoma. N Engl J Med. 2016; 375: 819-829.

[83] Pereira C, Gimenez-Xavier P, Pros E, et al. Genomic profiling of patient-derived xenografts for lung cancer identifies B2M inactivation impairing immunorecognition. Clin Cancer Res. 2017; 23: 3203-3213.

[84] Liu F, Zhong F, Wu H, et al. Prevalence and associations of beta2-microglobulin mutations in MSI-H/dMMR cancers. Oncologist. 2023; 28: e136-e144.

[85] Sade-Feldman M, Jiao YJ, Chen JH, et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun. 2017; 8: 1136.

[86] Kawazu M, Ueno T, Saeki K, et al. HLA class I analysis provides insight into the genetic and epigenetic background of immune evasion in colorectal cancer with high microsatellite instability. Gastroenterology. 2022; 162: 799-812.

[87] Garrido MA, Navarro-Ocon A, Ronco-Diaz V, Olea N, Aptsiauri N. Loss of heterozygosity (LOH) affecting HLA genes in breast cancer: clinical relevance and therapeutic opportunities. Genes (Basel). 2024; 15.

[88] Molina-Alejandre M, Perea F, Calvo V, et al. Perioperative chemoimmunotherapy induces strong immune responses and long-term survival in patients with HLA class I-deficient non-small cell lung cancer. J Immunother Cancer. 2024; 12.

[89] Sears T, Carter H. MHC hammer decodes HLA disruption in tumors. Cancer Res. 2025; 85: 642-643.

[90] Yeung JT, Hamilton RL, Ohnishi K, et al. LOH in the HLA class I region at 6p21 is associated with shorter survival in newly diagnosed adult glioblastoma. Clin Cancer Res. 2013; 19: 1816-1826.

[91] Jiang Z, Qin L, Tang Y, et al. Human induced-T-to-natural killer cells have potent anti-tumour activities. Biomark Res. 2022; 10: 13.

[92] Shao C, Tang B, Chu JCH, et al. Macrophage-engaging peptidic bispecific antibodies (pBsAbs) for immunotherapy via a facile bioconjugation strategy. Chem Sci. 2024; 15: 11272-11278.

[93] Wang Q, Bergholz JS, Ding L, et al. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nat Commun. 2022; 13: 3022.

[94] Boulanger DSM, Douglas LR, Duriez PJ, et al. Tapasin-mediated editing of the MHC I immunopeptidome is epitope specific and dependent on peptide off-rate, abundance, and level of tapasin expression. Front Immunol. 2022; 13: 956603.

[95] Unanue ER, Turk V, Neefjes J. Variations in MHC class II antigen processing and presentation in health and disease. Annu Rev Immunol. 2016; 34: 265-297.

[96] Mellins ED, Stern LJ. HLA-DM and HLA-DO, key regulators of MHC-II processing and presentation. Curr Opin Immunol. 2014; 26: 115-122.

[97] Shionoya Y, Kanaseki T, Miyamoto S, et al. Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition. Oncoimmunology. 2017; 6: e1274476.

[98] Qiu Z, Khalife J, Ethiraj P, et al. IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes. Sci Adv. 2024; 10: eadk2091.

[99] Wight J, Blombery P, Lickiss J, et al. Systemic diffuse large B-cell lymphoma involving the central nervous system has high rates of defective antigen presentation and immune surveillance. Haematologica. 2024; 109: 3013-3018.

[100] Racanelli V, Leone P, Frassanito MA, et al. Alterations in the antigen processing-presenting machinery of transformed plasma cells are associated with reduced recognition by CD8+ T cells and characterize the progression of MGUS to multiple myeloma. Blood. 2010; 115: 1185-1193.

[101] Lim WC, Marques Da Costa ME, Godefroy K, et al. Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers. Front Immunol. 2023; 14: 1265469.

[102] Ruterbusch M, Pruner KB, Shehata L, Pepper M. In vivo CD4(+) T cell differentiation and function: revisiting the Th1/Th2 paradigm. Annu Rev Immunol. 2020; 38: 705-725.

[103] Couture A, Garnier A, Docagne F, et al. HLA-Class II Artificial Antigen Presenting Cells in CD4(+). T Cell-Based Immunotherapy, Front Immunol. 2019; 10: 1081.

[104] Bawden EG, Wagner T, Schroder J, et al. CD4(+) T cell immunity against cutaneous melanoma encompasses multifaceted MHC II-dependent responses. Sci Immunol. 2024; 9: eadi9517.

[105] Seung E, Xing Z, Wu L, et al. A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells. Nature. 2022; 603: 328-334.

[106] Fukushima G, Sato E, Udo R, et al. Stromal CD4 (+) T cell subsets mediate antitumor cytotoxic immune responses in human colorectal carcinoma. Anticancer Res. 2024; 44: 3899-3906.

[107] Axelrod ML, Cook RS, Johnson DB, Balko JM. Biological consequences of MHC-II expression by tumor cells in cancer. Clin Cancer Res. 2019; 25: 2392-2402.

[108] Rocha N, Neefjes J. MHC class II molecules on the move for successful antigen presentation. EMBO J. 2008; 27: 1-5.

[109] Shin JS, Ebersold M, Pypaert M, Delamarre L, Hartley A, Mellman I. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature. 2006; 444: 115-118.

[110] Kim HJ, Bandola-Simon J, Ishido S, et al. Ubiquitination of MHC class II by march-I regulates dendritic cell fitness. J Immunol. 2021; 206: 494-504.

[111] Shmakova A, Hugot C, Kozhevnikova Y, Schwager Karpukhina A, et al. Chronic HIV-1 Tat action induces HLA-DR downregulation in B cells: a mechanism for lymphoma immune escape in people living with HIV. J Med Virol. 2024; 96: e29423.

[112] Lei PJ, Pereira ER, Andersson P, et al. Cancer cell plasticity and MHC-II-mediated immune tolerance promote breast cancer metastasis to lymph nodes. J Exp Med. 2023; 220.

[113] Johnson DB, Nixon MJ, Wang Y, et al. Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement. JCI Insight. 2018; 3.

[114] Forero A, Li Y, Chen D, et al. Expression of the MHC class II pathway in triple-negative breast cancer tumor cells is associated with a good prognosis and infiltrating lymphocytes. Cancer Immunol Res. 2016; 4: 390-399.

[115] Baleeiro RB, Bouwens CJ, Liu P, et al. MHC class II molecules on pancreatic cancer cells indicate a potential for neo-antigen-based immunotherapy. Oncoimmunology. 2022; 11: 2080329.

[116] Nagasaki J, Togashi Y, Sugawara T, et al. The critical role of CD4+ T cells in PD-1 blockade against MHC-II-expressing tumors such as classic Hodgkin lymphoma. Blood Adv. 2020; 4: 4069-4082.

[117] Zhao M, Flynt FL, Hong M, et al. MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-gamma. Mol Immunol. 2007; 44: 2923-2932.

[118] Zeng Z, Gu SS, Ouardaoui N, et al. Hippo signaling pathway regulates cancer cell-intrinsic MHC-II expression. Cancer Immunol Res. 2022; 10: 1559-1569.

[119] Johnson DB, Estrada MV, Salgado R, et al. Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun. 2016; 7: 10582.

[120] Pickles OJ, Wanigasooriya K, Ptasinska A, et al. MHC class II is induced by IFNgamma and follows three distinct patterns of expression in colorectal cancer organoids. Cancer Res Commun. 2023; 3: 1501-1513.

[121] Wu B, Wang Q, Li B, Jiang M. LAMTOR1 degrades MHC-II via the endocytic in hepatocellular carcinoma. Carcinogenesis. 2022; 43: 1059-1070.

[122] Zhi J, Zhang P, Zhang W, et al. Inhibition of BRAF sensitizes thyroid carcinoma to immunotherapy by enhancing tsMHCII-mediated immune recognition. J Clin Endocrinol Metab. 2021; 106: 91-107.

[123] Yang JB, Zhao ZB, Liu QZ, et al. FoxO1 is a regulator of MHC-II expression and anti-tumor effect of tumor-associated macrophages. Oncogene. 2018; 37: 1192-1204.

[124] Neuwelt AJ, Kimball AK, Johnson AM, et al. Cancer cell-intrinsic expression of MHC II in lung cancer cell lines is actively restricted by MEK/ERK signaling and epigenetic mechanisms. J Immunother Cancer. 2020; 8.

[125] Yang Z, Li F, Huang Y, et al. Dynamic tumor-specific MHC-II immuno-PET predicts the efficacy of checkpoint inhibitor immunotherapy in melanoma. J Nucl Med. 2022; 63: 1708-1714.

[126] Chan KL, Gomez J, Cardinez C, et al. Inhibition of the CtBP complex and FBXO11 enhances MHC class II expression and anti-cancer immune responses. Cancer Cell. 2022; 40: 1190-1206 e1199.

[127] Blum JS, Wearsch PA, Cresswell P. Pathways of antigen processing. Annu Rev Immunol. 2013; 31: 443-473.

[128] Lin P, Lin Y, Mai Z, et al. Targeting cancer with precision: strategical insights into TCR-engineered T cell therapies. Theranostics. 2025; 15: 300-323.

[129] Wen M, Li Y, Qin X, Qin B, Wang Q. Insight into cancer immunity: mHCs, immune cells and commensal microbiota. Cells. 2023; 12.

[130] Deng G, Zhou L, Wang B, et al. Targeting cathepsin B by cycloastragenol enhances antitumor immunity of CD8 T cells via inhibiting MHC-I degradation. J Immunother Cancer. 2022; 10.

[131] Li L, Zeng X, Chao Z, et al. Targeting Alpha-ketoglutarate disruption overcomes immunoevasion and improves PD-1 blockade immunotherapy in renal cell carcinoma. Adv Sci (Weinh). 2023; 10: e2301975.

[132] Dong W, He B, Cao Y, et al. Low-dose SAHA enhances CD8(+) T cell-mediated antitumor immunity by boosting MHC I expression in non-small cell lung cancer. Cell Oncol (Dordr). 2024.

[133] Santharam MA, Shukla A, Levesque D, et al. NLRC5-CIITA fusion protein as an effective inducer of MHC-I expression and antitumor immunity. Int J Mol Sci. 2023; 24.

[134] Zhang J, Guo H, Wang L, et al. Cediranib enhances the transcription of MHC-I by upregulating IRF-1. Biochem Pharmacol. 2024; 221: 116036.

[135] Rimando JC, Chendamarai E, Rettig MP, et al. Flotetuzumab and other T-cell immunotherapies upregulate MHC class II expression on acute myeloid leukemia cells. Blood. 2023; 141: 1718-1723.

[136] Zuo D, Zhu Y, Wang K, et al. A novel LAG3 neutralizing antibody improves cancer immunotherapy by dual inhibition of MHC-II and FGL1 ligand binding. Biomed Pharmacother. 2024; 175: 116782.

[137] Shi H, Medler D, Wang J, et al. Suppression of melanoma by mice lacking MHC-II: mechanisms and implications for cancer immunotherapy. J Exp Med. 2024; 221.

[138] Taylor BC, Sun X, Gonzalez-Ericsson PI, et al. NKG2A is a therapeutic vulnerability in immunotherapy resistant MHC-I heterogeneous triple-negative breast cancer. Cancer Discov. 2024; 14: 290-307.

[139] Zhang Z, Kong X, Ligtenberg MA, et al. RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells. Cell Rep Med. 2022; 3: 100655.

[140] Liu C, Xie J, Lin B, et al. Pan-cancer single-cell and spatial-resolved profiling reveals the immunosuppressive role of APOE+ macrophages in immune checkpoint inhibitor therapy. Adv Sci (Weinh). 2024; 11: e2401061.

[141] Pan Y, Yu Y, Wang X, Zhang T. Tumor-associated macrophages in tumor immunity. Front Immunol. 2020; 11: 583084.

[142] Yan S, Wan G. Tumor-associated macrophages in immunotherapy. FEBS J. 2021; 288: 6174-6186.

[143] Xu Y, Zeng Y, Xiao X, et al. Targeted imaging of tumor associated macrophages in breast cancer. BIO Integration. 2023; 4.

[144] Hofman T, Ng SW, Garces-Lazaro I, Heigwer F, Boutros M, Cerwenka A. IFNgamma mediates the resistance of tumor cells to distinct NK cell subsets. J Immunother Cancer. 2024; 12: e009410.

[145] Liu X, Hogg GD, Zuo C, et al. Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity. Cancer Cell. 2023; 41: 1073-1090 e1012.

[146] Liu X, Bao X, Hu M, et al. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature. 2020; 588: 693-698.

[147] Choudhury NJ, Lai WV, Makhnin A, et al. A phase I/II study of valemetostat (DS-3201b), an EZH1/2 inhibitor, in combination with irinotecan in patients with recurrent small-cell lung cancer. Clin Cancer Res. 2024; 30: 3697-3703.

[148] Jing Y, Jin X, Wang L, et al. Decitabine-based chemotherapy followed by haploidentical lymphocyte infusion improves the effectiveness in elderly patients with acute myeloid leukemia. Oncotarget. 2017; 8: 53654-53663.

[149] Bestion E, Rachid M, Tijeras-Raballand A, et al. Ezurpimtrostat, a palmitoyl-protein thioesterase-1 inhibitor, combined with PD-1 inhibition provides CD8(+) lymphocyte repopulation in Hepatocellular carcinoma. Target Oncol. 2024; 19: 95-106.

[150] Chan KL, Gomez J, Cardinez C, et al. Inhibition of the CtBP complex and FBXO11 enhances MHC class II expression and anti-cancer immune responses. Cancer Cell. 2022; 40: 1190-1206.e1199.

[151] Wu X, Li T, Jiang R, Yang X, Guo H, Yang R. Targeting MHC-I molecules for cancer: function, mechanism, and therapeutic prospects. Mol Cancer. 2023; 22: 194.

[152] Dai E, Zhu Z, Wahed S, Qu Z, Storkus WJ, Guo ZS. Epigenetic modulation of antitumor immunity for improved cancer immunotherapy. Mol Cancer. 2021; 20: 171.

[153] Ye D, Zhou S, Dai X, et al. Targeting the MHC-I endosomal-lysosomal trafficking pathway in cancer: from mechanism to immunotherapy. Biochim Biophys Acta Rev Cancer. 2024; 1879: 189161.

[154] Xie J, Ye F, Deng X, et al. Circular RNA: a promising new star of vaccine. J Transl Int Med. 2023; 11: 372-381.

[155] Cai YW, Liu CC, Zhang YW, et al. MAP3K1 mutations confer tumor immune heterogeneity in hormone receptor-positive HER2-negative breast cancer. J Clin Invest. 2024; 135: e183656.

[156] Cui Y, Zhang W, Zeng X, Yang Y, Park SJ, Nakai K. Computational analysis of the functional impact of MHC-II-expressing triple-negative breast cancer. Front Immunol. 2024; 15: 1497251.

[157] Radwan J, Babik W, Kaufman J, Lenz TL, Winternitz J. Advances in the evolutionary understanding of MHC polymorphism. Trends Genet. 2020; 36: 298-311.

[158] Abualrous ET, Sticht J, Freund C. Major histocompatibility complex (MHC) class I and class II proteins: impact of polymorphism on antigen presentation. Curr Opin Immunol. 2021; 70: 95-104.

[159] Sensi B, Angelico R, Toti L, et al. Mechanism, potential, and concerns of immunotherapy for hepatocellular carcinoma and liver transplantation. Curr Mol Pharmacol. 2024; 17: e18761429310703.

[160] Yu Q, Dong Y, Wang X, et al. Pharmacological induction of MHC-I expression in tumor cells revitalizes T cell antitumor immunity. JCI Insight. 2024; 9: e177788.

[161] Sun X, Watanabe T, Oda Y, et al. Targeted demethylation and activation of NLRC5 augment cancer immunogenicity through MHC class I. Proc Natl Acad Sci U S A. 2024; 121: e2310821121.

[162] Morton JJ, Bird G, Refaeli Y, Jimeno A. Humanized mouse xenograft models: narrowing the tumor-microenvironment gap. Cancer Res. 2016; 76: 6153-6158.

[163] Zhou Z, Van der Jeught K, Li Y, et al. A T cell-engaging tumor organoid platform for pancreatic cancer immunotherapy. Adv Sci (Weinh). 2023; 10: e2300548.

[164] Tu J, Xu H, Ma L, et al. Nintedanib enhances the efficacy of PD-L1 blockade by upregulating MHC-I and PD-L1 expression in tumor cells. Theranostics. 2022; 12: 747-766.

[165] Sanmamed MF, Pastor F, Rodriguez A, et al. Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol. 2015; 42: 640-655.

[166] Reithofer M, Rosskopf S, Leitner J, et al. 4-1BB costimulation promotes bystander activation of human CD8 T cells. Eur J Immunol. 2021; 51: 721-733.

[167] Zhou X, Jia X, Huang Z, et al. MHC class II regulation of CD8(+) T cell tolerance and implications in autoimmunity and cancer immunotherapy. Cell Rep. 2023; 42: 113452.

[168] Cheng B, Pan W, Xiao Y, et al. HDAC-targeting epigenetic modulators for cancer immunotherapy. Eur J Med Chem. 2024; 265: 116129.

[169] Tufail M, Jiang CH, Li N. Altered metabolism in cancer: insights into energy pathways and therapeutic targets. Mol Cancer. 2024; 23: 203.

[170] Song P, Han X, Zheng R, et al. Upregulation of MHC-I and downregulation of PD-L1 expression by doxorubicin and deferasirox codelivered liposomal nanoparticles for chemoimmunotherapy of melanoma. Int J Pharm. 2022; 624: 122002.

[171] Zheng P, Wang G, Liu B, Ding H, Ding B, Lin J. Succinate nanomaterials boost tumor immunotherapy via activating cell pyroptosis and enhancing MHC-I expression. J Am Chem Soc. 2025; 147: 1508-1517.

[172] Zheng S, Liang JY, Tang Y, et al. Dissecting the role of cancer-associated fibroblast-derived biglycan as a potential therapeutic target in immunotherapy resistance: a tumor bulk and single-cell transcriptomic study. Clin Transl Med. 2023; 13: e1189.

[173] Xie J, Lin X, Deng X, et al. Cancer-associated fibroblast-derived extracellular vesicles: regulators and therapeutic targets in the tumor microenvironment. Cancer Drug Resist. 2025; 8: 2.

[174] Liu H, Li Y, Karsidag M, Tu T, Wang P. Technical and biological biases in bulk transcriptomic data mining for cancer research. J Cancer. 2025; 16: 34-43.

[175] Liu H, Guo Z, Wang P. Genetic expression in cancer research: challenges and complexity. Gene Reports. 2024; 37: 102042.

[176] Ito Y, Pan D, Zhang W, et al. Addressing tumor heterogeneity by sensitizing resistant cancer cells to T cell-secreted cytokines. Cancer Discov. 2023; 13: 1186-1209.

[177] Nojima Y, Yao R, Suzuki T. Single-cell RNA sequencing and machine learning provide candidate drugs against drug-tolerant persister cells in colorectal cancer. Biochim Biophys Acta Mol Basis Dis. 2025; 1871: 167693.

[178] Liu H, Dong A, Rasteh AM, Wang P, Weng J. Identification of the novel exhausted T cell CD8 + markers in breast cancer. Sci Rep. 2024; 14: 19142.

[179] Liu H, Hamaia SW, Dobson L, et al. The voltage-gated sodium channel β3 subunit modulates C6 glioma cell motility independently of channel activity. Biochim Biophys Acta Mol Basis Dis. 2025; 1871: 167844.

[180] Liu H, Li Y. Potential roles of Cornichon family AMPA receptor auxiliary protein 4 (CNIH4) in head and neck squamous cell carcinoma. Cancer Biomark. 2022; 35: 439-450.

[181] Li Y, Liu H. Clinical powers of aminoacyl tRNA synthetase complex interacting multifunctional protein 1 (AIMP1) for head-neck squamous cell carcinoma. Cancer Biomark. 2022; 34: 359-374.

[182] Li C, Guo H, Zhai P, et al. Spatial and Single-cell transcriptomics reveal a cancer-associated fibroblast subset in HNSCC that restricts infiltration and antitumor activity of CD8+ T cells. Cancer Res. 2024; 84: 258-275.

[183] Huang H, Sikora MJ, Islam S, et al. Select sequencing of clonally expanded CD8(+) T cells reveals limits to clonal expansion. Proc Natl Acad Sci U S A. 2019; 116: 8995-9001.

[184] Feng DC, Zhu WZ, Wang J, et al. The implications of single-cell RNA-seq analysis in prostate cancer: unraveling tumor heterogeneity, therapeutic implications and pathways towards personalized therapy. Mil Med Res. 2024; 11: 21.

[185] Zhang Y, Wang D, Peng M, et al. Single-cell RNA sequencing in cancer research. J Exp Clin Cancer Res. 2021; 40: 81.

[186] Tietscher S, Wagner J, Anzeneder T, et al. A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer. Nat Commun. 2023; 14: 98.

[187] Liu H, Wang P. CRISPR screening and cell line IC50 data reveal novel key genes for trametinib resistance. Clin Exp Med. 2024; 25: 21.

[188] Burr ML, Sparbier CE, Chan KL, et al. An evolutionarily conserved function of polycomb silences the MHC Class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell. 2019; 36: 385-401.e388.

[189] Feng HR, Shen XN, Zhu XM, et al. Unveiling major histocompatibility complex-mediated pan-cancer immune features by integrated single-cell and bulk RNA sequencing. Cancer Lett. 2024; 597: 217062.

[190] Algarra I, Garrido F, Garcia-Lora AM. MHC heterogeneity and response of metastases to immunotherapy. Cancer Metastasis Rev. 2021; 40: 501-517.

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