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

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-07-17 DOI:10.1002/ctm2.70403

Pei Lin, Yunfan Lin, Xu Chen, Xinyuan Zhao, Li Cui

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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.

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.

Abstract Image

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解码MHC损失：癌症免疫抵抗的分子机制和意义

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免疫治疗干预抗性的关键机制。这篇综述的重点是中央调控途径。这些包括转录抑制、溶酶体降解和翻译后修饰，这些修饰会破坏MHC的稳定性、运输和表面表达。我们强调这些机制如何损害抗原呈递和促进肿瘤免疫逃避。此外，我们探索了新兴的治疗策略，重点是重新激活MHC表达，以增强肿瘤的免疫原性，提高免疫治疗的疗效。最后，我们讨论了这些方法的转化潜力和剩余的挑战，包括肿瘤异质性、免疫毒性和肿瘤微环境内的动态调节，必须解决这些问题，以优化mhc靶向干预在癌症免疫治疗中。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以上调MHC表达，改善T细胞活化。联合策略通过重新激活肿瘤免疫原性来增强免疫治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.