Immunopharmacology of GPR35: Context-driven signaling and functional plasticity in host defense

GPR35 is an emerging orphan G protein-coupled receptor (GPCR) that plays pivotal roles in immune cells, epithelial cells, mesenchymal cell, parenchymal cell, and neuron cells, involved in various physiological and pathological processes. Despite growing interest, GPR35-targeted agents have yet to achieve successful clinical translation. In this review, we proposed a new model wherein GPR35 functions as a multiple sensor that integrates fluctuating metabolic signals to fine-tune immune response and tissue homeostasis in a context- and cell type-dependent manner, thus facilitating host defense mechanism. We synthesized the landscape of endogenous GPR35 ligands, including tryptophan and tyrosine metabolites, and lipid derivatives. We further illustrate its remarkable signaling plasticity, including canonical GPCR signaling as well as non-canonical interactions, which enables its cell type-specific and context-dependent functions. This review demonstrates how the receptor engaged in inflammation associated diseases, including colitis, neuroinflammation, inflammatory pain, cardiovascular disease, metabolic disease, and cancers. For development for GPR35 immunopharmacology, this review critically evaluated the therapeutic landscape of GPR35 modulators, analyzing their structural features, downstream effects, and therapeutic rationale. We argue that harnessing the therapeutic potential of GPR35 requires moving beyond conventional agonist and antagonist toward signaling-biased and cell type- or tissue-selective strategies. By bridging mechanistic insights with translational perspectives, this review provides a roadmap for the rational development of next-generation GPR35-targeted therapeutics.