Volume 15, Issue 7 e70403
REVIEW
Open Access

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

Pei Lin

Pei Lin

School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China

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Yunfan Lin

Yunfan Lin

School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China

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Xu Chen

Xu Chen

School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China

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Xinyuan Zhao

Corresponding Author

Xinyuan Zhao

School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China

Correspondence

Xinyuan Zhao and Li Cui, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China.

Email: [email protected] and [email protected]

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Li Cui

Corresponding Author

Li Cui

School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China

School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA

Correspondence

Xinyuan Zhao and Li Cui, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China.

Email: [email protected] and [email protected]

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First published: 17 July 2025

Pei Lin and Yunfan Lin have contributed equally to this work.

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.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

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