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Peptide-MHC I regulatory mechanisms and intervention strategies in anti-tumor T cell immunity

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

T cell immune responses are triggered by antigenic peptides presented through major histocompatibility complex class Is (pMHC-Is), which play an important role in the genesis, development, and therapy of tumors. The capacity of a specific pMHC-I to elicit T cell responses is deeply influenced by its expression level (quantity) and its immunogenicity (quality). Tumor cells can evade T cell immunity by down-regulating the quantity of pMHC-Is or selectively eliminating highly immunogenic antigenic peptides. Augmenting the quantity or quality of pMHC-Is is essential for tumor immunotherapy. However, the complexity of pMHC-I regulation and tumor heterogeneity pose challenges to clinical strategies. Consequently, developing approaches grounded in comprehensive analyses of pMHC-I regulatory mechanisms remains a focal point in the research of T cell immunity. In this review, we discuss how tumors modulate their surface pMHC-Is through genetic, epigenetic, and proteomic mechanisms and summarize potential therapeutic strategies targeting these mechanisms, which may provide a valuable reference for the development of novel tumor immunotherapies based on pMHC-I modulation.

Tumor cells can achieve immune escape by interfering with the quantity and quality of pMHC-Is, and corresponding immunotherapy can also be achieved by the regulation of pMHC-Is.

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Fig. 1: Tumor antigen presentation and its regulatory mechanisms.
Fig. 2: Comparison of RNA expression levels of HLA-A between different tumors and tissues.
Fig. 3: Therapeutic approaches against the down-regulation of pMHC-I expression.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82204413, 82304361 and 82473827), the Zhejiang Provincial Natural Science Foundation (LR22H310002 and LQ23H300004). Figures for this article were created with BioRender.com.

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Author notes

  1. These authors contributed equally: Zhi-chao Zhang, Ying Shen, Yu-shen Lin

Authors and Affiliations

  1. Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, China

    Zhi-chao Zhang, Ying Shen, Yu-shen Lin, Bo Yang, Ji Cao & Wen-bin Zhao

  2. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Zhi-chao Zhang, Ying Shen, Yu-shen Lin, Bo Yang, Ji Cao & Wen-bin Zhao

  3. Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, 310018, China

    Ying Shen, Bo Yang, Ji Cao & Wen-bin Zhao

  4. School of Medicine, Hangzhou City University, Hangzhou, 310015, China

    Bo Yang

  5. Cancer Center, Zhejiang University, Hangzhou, 310058, China

    Ji Cao & Jun Li

  6. Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, 310009, China

    Jun Li

  7. Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, 310000, China

    Jun Li

  8. The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China

    Jun Li

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  1. Zhi-chao Zhang
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  3. Yu-shen Lin
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Correspondence to Ji Cao, Jun Li or Wen-bin Zhao.

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Zhang, Zc., Shen, Y., Lin, Ys. et al. Peptide-MHC I regulatory mechanisms and intervention strategies in anti-tumor T cell immunity. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01574-y

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