The role of MHC molecules in cancer immunotherapy: Insights into tumor immune evasion and therapeutic strategies

Abstract

Major histocompatibility complex (MHC) molecules, as core mediators of antigen presentation in the immune system, play pivotal roles in activating anti-tumor immune responses by presenting antigens to CD8⁺ and CD4⁺ T cells. However, tumor cells and immunosuppressive cells within the tumor microenvironment (TME) employ multi-dimensional mechanisms to dysregulate MHC expression and function—including epigenetic silencing, autophagic degradation, and interference with transcription factors such as NLRC5 (for MHC-I) and CIITA (for MHC-II). These mechanisms enable immune escape and limit the efficacy of cancer immunotherapy. Additionally, we review MHC-based therapeutic strategies—such as cytokine therapy, TCR-T cell therapy, immune checkpoint inhibitor (ICI) combination therapy, and tumor vaccine therapies—that have been developed to restore MHC function and overcome immune escape. A deeper understanding of the regulatory networks governing MHC molecules in tumor immunity will provide critical insights for the development of precise and effective immunotherapeutic strategies, ultimately improving clinical outcomes for cancer patients.