The non-classical immune checkpoint HLA-G: a regulatory master switch governing tolerance, evasion, and translational frontiers

Human Leukocyte Antigen G (HLA-G), a non-classical MHC Class I molecule, plays a pivotal role in immune regulation, particularly in reproductive immunology. It functions as an immune checkpoint by interacting with inhibitory receptors such as LILRB1 (ILT2/CD85j) and LILRB2 (ILT4/CD85d) on both innate and adaptive immune cells. HLA-G is crucial for maintaining immune tolerance, with its expression by extravillous trophoblasts being essential for fetal survival and establishing materno-fetal immune privilege. In transplantation, HLA-G promotes graft acceptance and serves as a positive prognostic marker. However, its tolerogenic function is exploited by malignant cells to evade immune detection, inhibiting cytotoxic T-lymphocyte (CTL) and NK cell functions, inducing regulatory Treg cells, and remodeling the tumor microenvironment (TME). Elevated HLA-G expression correlates with poor prognosis in various cancers, with a meta-analysis showing a Hazard Ratio for mortality of 2.09. HLA-G's soluble isoforms (sHLA-G) and exosome-mediated HLA-Gev (HLA-G-bearing extracellular vesicles) transfer are emerging as potential liquid biopsy markers. Targeting the HLA-G/ILT axis is a promising therapeutic strategy, with clinical trials underway using anti-HLA-G antibodies (e.g., TTX-080) and anti-LILRB1 antibodies (e.g., BND-22), often combined with PD-1/PD-L1 inhibitors. Additionally, HLA-G agonists or engineered cells are being explored for inducing tolerance in autoimmune diseases and transplantation.