Unlocking the promise of innate biology through the HLA-G/ILT2/ILT4 pathway.

Inhibitory immune pathways have gained considerable attention following the clinical success of immune checkpoint inhibitors in cancer. While much focus has been placed on classical checkpoints such as programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4), alternative immunosuppressive mechanisms are increasingly recognized as contributors to immune evasion, tumor progression, and therapeutic resistance. Among these, non-classical human leukocyte antigens (HLAs), particularly HLA-G and its receptors ILT2 and ILT4, have emerged as key players regulating antitumor responses.This review highlights the HLA-G/ILT2/ILT4 axis as a distinct immunosuppressive pathway within the HLA family promoting immune escape. This pathway engages natural killer (NK) cells, myeloid cells, and antigen-experienced T cells through unique mechanisms and is characterized by effects on immune cell subsets and tumor expression profiles that are largely non-overlapping with PD-L1 and CTLA-4. These distinguishing features underscore its potential as a novel and promising pathway to expand the scope of immune checkpoint-based interventions.Although early-phase clinical studies have begun to explore this axis, robust evidence of therapeutic efficacy remains limited. Constraints such as small sample sizes, heavily pretreated patient populations, and an emphasis on PD-1 combinations in PD-1/PD-L1 inhibitor-experienced patients may have hindered a clear assessment of its potential. Nonetheless, the unique biology of this pathway supports its potential as a novel target for cancer therapeutics. Continued research is needed to refine tumor subtypes, identify responsive patient subsets, and clarify their therapeutic relevance.