REVIEW article
Front. Oncol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicNew Tumor Immune Checkpoints and Their Applications in Tumor ImmunotherapyView all 12 articles
The Non-Classical Immune Checkpoint HLA-G: A Regulatory Master Switch Governing Tolerance, Evasion, and Translational Frontiers
Provisionally accepted
- Zhengzhou Health College, Zhengzhou, China
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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.
Keywords: cancer immunotherapy, HLA-G, Immune checkpoint, Immune Tolerance, immuneevasion
Received: 05 Dec 2025; Accepted: 04 Feb 2026.
Copyright: © 2026 Liu, Li, Li, Xue, Xue and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Huan Liu
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