From orphan to oncogene: The role of GPR35 in cancer and immune modulation.

G protein-coupled receptors (GPCRs) are well-studied and the most traceable cell surface receptors for drug discovery. One of the intriguing members of this family is G protein-coupled receptors 35 (GPR35), which belongs to the class A rhodopsin-like family of GPCRs identified over two decades ago. GPR35 presents interesting features such as ubiquitous expression and distinct isoforms. Moreover, functional and genome-wide association studies on its widespread expression have linked GPR35 with pathophysiological disease progression. Various pieces of evidence have been accumulated regarding the independent or endogenous ligand-dependent role of GPR35 in cancer progression and metastasis. In the current scenario, the relationship of this versatile receptor and its putative endogenous ligands for the activation of oncogenic signal transduction pathways at the cellular level is an active area of research. These intriguing features offered by GPR35 make it an oncological target, justifying its uniqueness at the physiological and pathophysiological levels concerning other GPCRs. For pharmacologically targeting receptor-induced signaling, few potential competitive antagonists have been discovered that offer high selectivity at a human level. In addition to its fascinating features, targeting GPR35 at rodent and human orthologue levels is distinct, thus contributing to the sub-species selectivity. Strategies to modulate these issues will help us understand and truly target GPR35 at the therapeutic level. In this article, we have provided prospects on each topic mentioned above and suggestions to overcome the challenges. This review discusses the molecular mechanism and signal transduction pathways activated by endogenous ligands or spontaneous auto-activation of GPR35 that contributes towards disease progression. Furthermore, we have highlighted the GPR35 structure, ubiquitous expression, its role in immunomodulation, and at the pathophysiological level, especially in cancer, indicating its status as a versatile receptor. Subsequently, we discussed the various proposed ligands and their mechanism of interaction with GPR35. Additionally, we have summarized the GPR35 antagonist that provides insights into the opportunities for therapeutically targeting this receptor.