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

Pei Lin1, Yunfan Lin1, Xu Chen1

  • 1School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Clinical and Translational Medicine
|July 17, 2025
PubMed

Insights

Tumours evade immune detection by reducing major histocompatibility complex (MHC) expression. Reactivating MHC expression through novel therapies can enhance anti-tumour immunity and improve cancer immunotherapy outcomes.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Downregulation of Major Histocompatibility Complex (MHC) molecules is a critical immune evasion strategy employed by tumors.
  • This downregulation impairs tumor antigen presentation, hindering immune recognition and response.

Purpose of the Study:

  • To review the central regulatory pathways involved in MHC downregulation in cancer.
  • To explore therapeutic strategies aimed at restoring MHC expression for enhanced cancer immunotherapy.

Main Methods:

  • Review of literature focusing on transcriptional repression, lysosomal degradation, and post-translational modifications affecting MHC.
  • Analysis of emerging therapeutic interventions targeting MHC reactivation.

Main Results:

  • Identified key mechanisms of MHC loss including transcriptional repression, lysosomal degradation, and post-translational modifications.
  • Highlighted the potential of epigenetic and metabolic modulators to upregulate MHC expression and improve T cell activation.

Conclusions:

  • Restoring MHC expression is a promising strategy to enhance tumor immunogenicity and overcome resistance to immunotherapy.
  • Combination strategies targeting MHC hold significant translational potential but require addressing challenges like tumor heterogeneity and immunotoxicity.
Keywords:
MHC losscancer immunotherapyimmune responsestumour microenvironment

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