Nonclassical MHC‐I Molecules: Emerging Therapeutic Targets in Next‐Generation Immunotherapy

Immunotherapies have transformed the treatment of cancers and infectious diseases by harnessing the precision and adaptability of the immune system. Central to these advances is the major histocompatibility complex (MHC) system, with classical MHC-I molecules well documented for their role in immune surveillance. MHC-dependent therapies, including immune checkpoint blockade (ICB), T cell receptor (TCR)-engineered therapies, and cancer vaccines, have shown substantial clinical promise. However, their broader efficacy is hindered by the extreme polymorphism of classical MHC-I molecules, susceptibility to immune evasion, and frequent downregulation in many disease settings. In contrast, nonclassical MHC-I molecules, including HLA-E, HLA-F, HLA-G, CD1, and MR1, offer alternative therapeutic opportunities. Shaped by strong evolutionary conservation, these molecules exhibit limited polymorphism, specialized antigen repertoires, distinct trafficking behaviors, and the capability to engage both innate and adaptive immune cells. In this review, we synthesize current knowledge of the structural biology, antigen presentation pathways, receptor interactions, and immunoregulatory functions of nonclassical MHC-I molecules. We further highlight emerging therapeutic strategies, including immune checkpoint modulation, cargo-based ligands, conformation-specific biologics, vaccines, and cellular therapies, while critically evaluating translational challenges. By linking specialized structural and functional features to therapeutic design, this review provides a unified framework for exploiting nonclassical MHC-I molecules as next-generation targets in immunotherapy.