GPR65 in cancer: expression heterogeneity, invasion and metastasis, the tumor immune microenvironment, and translational implications.

GPR65, also known as TDAG8, is a proton-sensing G protein-coupled receptor that links extracellular acidosis to intracellular signaling. Because acidic stress is a prominent feature of the tumor microenvironment, GPR65 has emerged as a potential regulator of tumor progression, immune suppression, and therapeutic response. However, its biological effects vary across tumor types and depend on the dominant GPR65-expressing compartment, microenvironmental context, and downstream signaling output. In this review, we summarize current evidence on GPR65 in cancer from an immunopharmacological perspective. We discuss its molecular characteristics and proton-induced Gs-cAMP-PKA signaling, then examine tumor cell-intrinsic and immune-mediated functions, including acid-adaptive survival, macrophage polarization, CD8+ T-cell dysfunction, and broader remodeling of the tumor immune microenvironment. We further reconcile apparently divergent findings across glioma, melanoma, lung cancer, colorectal cancer, osteosarcoma, and other malignancies using a context-dependent framework. GPR65-targeted therapy is beginning to enter clinical translation. The oral inhibitor PTT-4256 is undergoing Phase 1/2 evaluation in RAISIC-1, with updated first-in-human data providing preliminary pharmacokinetic, pharmacodynamic, biomarker, safety, and early signals of clinical activity. A grade 5 multiple-organ-failure dose-limiting toxicity, deemed probably related to the study drug, was reported at the 300-mg dose level, after which further exploration of this dose was discontinued. The optimal dose, overall safety profile, and definitive clinical antitumor efficacy remain to be established. Further single-cell, spatial, and biomarker-guided studies will be essential to define the therapeutic value of GPR65.