Harnessing the Immunomodulatory Properties of HLA-G for Advanced Immunotherapies

Xeni Beli¹Nikolaos Savvopoulos¹Dionysia Kefala²Memnon Lysandrou³Maria Liga¹Alexandros Spyridonidis^1*

• ¹Bone Marrow Transplantation Unit and Institute of Cell Therapy, University of Patras, Patras, Greece
• ²Department of Hematology, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, Netherlands
• ³Department of Medicine I, Medical Center University of Freiburg, Faculty of Medicine, Albert-Ludwigs-Universitat Freiburg, Freiburg, Germany

Human leukocyte antigen-G (HLA-G) is a non-classical MHC class I molecule with unique 17 immunomodulatory properties that extend far beyond its well-established role at the maternal-fetal 18 interface. Increasing evidence highlights HLA-G as a pivotal regulator of immune homeostasis, 19 capable of shaping both innate and adaptive cytotoxic responses. It exerts a context-dependent role, 20 promoting tolerance in settings such as transplantation and autoimmunity while contributing to 21 immune evasion in cancer and infection, and this functional plasticity is further shaped by its isoform 22 diversity and its interplay with other non-classical HLA class I molecules. In this review, we discuss 23 key aspects of HLA-G biology, particularly its capacity to promote immune tolerance or facilitate 24 immune escape, and how these insights can be leveraged in the development of cellular and acellular 25 immunotherapies. We further summarize current strategies that incorporate or target HLA-G in the 26 treatment of malignancies and autoimmune diseases, and highlight its emerging potential as a 27 therapeutic target.