The GPR183-oxysterol axis in cancer: immune trafficking, spatial organization, and therapeutic potential

G protein-coupled receptor 183 (GPR183; also known as EBI2, Epstein-Barr virus-induced G-protein-coupled receptor 2) has emerged as a central regulator linking 7α,25-dihydroxycholesterol (7α,25-OHC) gradients to immune cell trafficking and tissue organization. In this review, we synthesize the structural, physiological, and oncogenic dimensions of the GPR183 axis. We first discuss the enzymatic biogenesis of its oxysterol ligand and the structural mechanisms underlying receptor activation. We then examine the context-dependent roles of GPR183 within the tumor microenvironment (TME), including receptor antagonism in hematological malignancies, modulation of immune organization in immunologically cold solid tumors. We further review the emerging relevance of spatial GPR183 profiling in relation to immune checkpoint blockade (ICB) responsiveness, as well as recent synthetic immunology strategies aimed at enhancing chimeric antigen receptor T (CAR-T) cell trafficking through oxysterol sensing. We identify and systematically analyze the central paradox of the GPR183 axis - namely, that identical 7α,25-OHC gradients can drive either anti-tumor tertiary lymphoid structure (TLS) formation or pro-tumor immunosuppressive myeloid cell recruitment - and discuss the potential determinants of this contextual polarity, including ligand concentration thresholds, spatial compartmentalization of oxysterol production, and receptor co-expression patterns. Collectively, current advances in the GPR183-oxysterol axis delineate new opportunities for metabolism-oriented immunotherapy and precision oncology.