Advancing human leukocyte antigen-based cancer immunotherapy: from personalized to broad-spectrum strategies for genetically heterogeneous populations

Human leukocyte antigen (HLA)-based immunotherapeutics, such as tebentafusp-tebn and afamitresgene autoleucel, have expanded the treatment options for HLA-A*02-positive patients with rare solid tumors such as uveal melanoma, synovial sarcoma, and myxoid liposarcoma. Unfortunately, many patients of European, Latino/Hispanic, African, Asian, and Native American ancestry who carry non-HLA-A*02 alleles remain largely ineligible for most current HLA-based immunotherapies. This comprehensive review introduces HLA allotype-driven cancer health disparities (HACHD) as an emerging research focus, and examines how past and current HLA-targeted immunotherapeutic strategies may have inadvertently contributed to cancer health disparities. We discuss several preclinical and clinical strategies, including the incorporation of artificial intelligence (AI), to address HACHD. Last, we emphasize the urgent need for further research to better understand HLA allotype heterogeneity and its influence on tumor immunopeptidome-driven immune responses. We anticipate that these strategies will accelerate the development and implementation of both personalized and broad-spectrum HLA-based immunotherapies, and will ultimately improve cancer treatment across genetically heterogeneous patient populations worldwide.