Human leukocyte antigen-G in solid tumors: from immunotolerance to immunotherapy

Immune checkpoint-targeted immunotherapy has achieved unprecedented success, yet its limitations remain evident. Human leukocyte antigen-G (HLA-G), a novel immune checkpoint, exhibits restricted physiologic expression but is broadly expressed in various tumors, conferring systemic immune suppressive functions via different types of immune inhibitory receptors, and is associated with a poor prognosis for patients with cancer, making it an attractive tumor-site-agnostic candidate target for cancer immunotherapy. Since 2020, clinical trials employing different strategies of HLA-G-targeted immunotherapy for various advanced solid cancers have been conducted. Herein, the molecular characteristics of HLA-G, HLA-G-receptor binding interactions, and HLA-G-targeted preclinical investigations and clinical trials for solid cancer immunotherapy are highlighted, and the challenges associated with translating these findings into clinical settings are also discussed.