Role of HLA Class I Molecule in Cancer: Implications for Cancer Immunotherapy
Josiah Stephen
Neonatal Unit, Royal Bolton Hospital, Minerva Road, Bolton, England.
Ikechukwu Kanu
Department of Chemistry, Ball State University, Muncie Indiana, US State.
Nwamaka Nneka Onyedum
Haematology Department, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria.
Enibokun Theresa Orobator
College of Medicine and Veterinary Medicine, Global Health and Infectious Diseases, University of Edinburgh, United Kingdom.
Catherine Rono
Department of Immunology; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Ngwoke, Chinaza Faith
School of Pharmacy and Health Sciences, United States International University - Africa Nairobi, Kenya.
Victor Omeiza David
Department of Neurosurgery, Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom.
Wonderful Oluwatoyin Anosike
Cumbria, Nurthumberland, Tyne and Wear NHS Foundation Trust, England.
Lawrence John Ajutor
*
Department of Medical Laboratory Science, University of Benin, Edo State, Nigeria, England.
*Author to whom correspondence should be addressed.
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.
Keywords: HLA Class I Molecules, immunotherapy, tumour immune evasion, antigen presentation, major histocompatibility complexes