Perturbed MHC Class I Antigen Presentation Drives Cancer Immune Evasion Through Four Key Mechanisms

Cancer cells often evade immune surveillance by altering their antigen presentation machinery, a critical component for activating adaptive T cell responses. The Major Histocompatibility Complex class I (MHC Class I) system is central to this, presenting intracellular peptide antigens to cytotoxic T lymphocytes. When this system is compromised, T cells fail to recognize and eliminate cancerous cells, leading to disease progression. Understanding the specific mechanisms by which cancer perturbs MHC Class I is crucial for developing effective immunotherapies and cancer vaccines.

This review systematically analyzed existing literature on MHC Class I antigen presentation and its role in cancer. Researchers synthesized findings across numerous studies, categorizing perturbations into four distinct mechanistic levels: peptide generation, peptide loading, MHC Class I integrity, and epigenetic regulation. The aim was to provide an integrated view of their functional impact on immune recognition, thereby supporting therapeutic efforts to target antigen presentation or exploit these alterations in cancer. The authors did not conduct new experiments but rather consolidated existing knowledge.

The review identified four primary mechanistic levels through which MHC Class I antigen presentation is perturbed in cancer, leading to compromised immune function. These include issues with peptide generation, where tumor cells may alter proteasome activity or antigen processing to produce fewer or altered immunogenic peptides. Perturbations in peptide loading involve defects in TAP transporters or tapasin, hindering the efficient loading of peptides onto MHC Class I molecules in the endoplasmic reticulum. MHC Class I integrity can be compromised through reduced surface expression, internalization, or degradation, directly limiting the number of antigen-presenting molecules available for T cell recognition. Finally, epigenetic regulation, such as DNA methylation or histone modification, can silence genes encoding MHC Class I components or associated machinery. These multifaceted perturbations collectively contribute to the immune evasion phenotype observed in various cancers.

The review highlights that these four categories of MHC Class I perturbation offer distinct targets for therapeutic intervention, emphasizing the need for strategies that restore or bypass these defects to enhance anti-tumor immunity.