Lin Pei, Lin Yunfan, Chen Xu, Zhao Xinyuan, Cui Li
School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China.
School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA.
Clin Transl Med. 2025 Jul;15(7):e70403. doi: 10.1002/ctm2.70403.
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. HIGHLIGHTS: Tumour cells evade immune surveillance by downregulating MHC expression through transcriptional repression, lysosomal degradation and post-translational modifications. Pharmacological agents interventing epigenetic and metabolic can upregulate MHC expression and improve T cell activation. Combination strategies potentiate immunotherapy efficacy by reinvigorating tumour immunogenicity.
主要组织相容性复合体（MHC）分子的缺失或下调是肿瘤逃避免疫识别并获得对免疫治疗干预耐药性的关键机制。本综述聚焦于核心调控途径。这些途径包括转录抑制、溶酶体降解以及破坏MHC稳定性、转运和表面表达的翻译后修饰。我们强调这些机制如何损害抗原呈递并促进肿瘤免疫逃逸。此外，我们探讨了旨在重新激活MHC表达以增强肿瘤免疫原性和提高免疫治疗疗效的新兴治疗策略。最后，我们讨论了这些方法的转化潜力以及剩余的挑战，包括肿瘤异质性、免疫毒性和肿瘤微环境内的动态调节，要优化癌症免疫治疗中针对MHC的干预措施，就必须解决这些问题。要点：肿瘤细胞通过转录抑制、溶酶体降解和翻译后修饰下调MHC表达来逃避免疫监视。干预表观遗传和代谢的药物可上调MHC表达并改善T细胞活化。联合策略通过恢复肿瘤免疫原性增强免疫治疗疗效。
Zotero 插件
