Emerging therapeutic opportunities targeting nonclassical MHC-I molecules.

Nonclassical major histocompatibility complex class I (MHC-I) molecules, including human leukocyte antigen E (HLA-E), HLA-F, HLA-G, MHC-I-related protein 1 (MR1), and the CD1 family, constitute a conserved antigen-presenting system that regulates immune surveillance, tissue homeostasis, and tolerance through specialized interactions with innate and unconventional T cells. Although these molecules have long been implicated in cancer, infection, autoimmunity, and transplantation, their distinct immunobiology and therapeutic potential have largely been considered in isolation. Recent advances in structural immunology, single-cell and spatial profiling, engineered immune cell technologies, and early clinical studies have established nonclassical MHC-I pathways as tractable targets for immunotherapy. In this review, we synthesize the biology, disease-associated functions, and therapeutic targeting of these molecules, integrating immune checkpoint blockade, antibody-based therapeutics, and MR1- and CD1-restricted cellular immunotherapies into a unified framework. We further highlight shared immunological principles, emerging clinical translation, and opportunities for universal, off-the-shelf immune interventions.