Role of HLA Class I Molecule in Cancer: Implications for Cancer Immunotherapy

Abstract

HLA class I molecules are essential for presenting tumour antigens to cytotoxic T-cells, but their dysregulation in cancer enables immune evasion and limiting the efficacy of immunotherapies for cancer. The objective of this review is to explore the function of HLA class I changes in cancer development and their consequences for immunotherapy evolution. Examining peer-reviewed studies from 2010–2025 in PubMed and Scopus, a thorough literature review was done with a focus toward HLA class I expression, genetic defects, and immunotherapy outcomes in cancers including melanoma and lung cancer. HLA Class I Downregulation is a hallmark of tumour cells. Findings show that epigenetic silencing, β2-microglobulin mutations, or altered antigen-processing machinery are identified as the major mechanisms of HLA downregulation observed in 50–70% of tumours. These alterations are primary to therapeutic implications like poor responses to drugs like checkpoint inhibitors and they cause decreased T-cell infiltration. Research shows that in preclinical models, restoring HLA class I expression through cytokines, epigenetic modulators, or gene therapy are effective strategies in T-cell recognition and tumour clearance. Combining such approaches with PD-1/PD-L1 inhibitors produces synergistic effects that raise response rates by 20–40%. Furthermore, HLA class I status assessment can serve as an emerging possible biomarker for immunotherapy success. However, tumour heterogeneity and immunosuppressive microenvironments remain a challenge. Crucially, clinical studies to validate HLA class I restoration strategies and biomarker-driven patient stratification are underway to Investigate interactions between natural killer cell responses and HLA class I to help improve therapeutic approaches. Targeting therapies to reverse HLA class I defects through oncolytic viruses, along with integrating these with tailored immunotherapies are suggested future directions in immunotherapy.