GPCRs in CAR‐T Cell Immunotherapy: Expanding the Target Landscape and Enhancing Therapeutic Efficacy

Chimeric Antigen Receptor T cell (CAR-T) therapy has shown significant efficacy in treating hematologic malignancies. However, its application in solid tumors is still challenged by a scarcity of specific targets and the immunosuppressive tumor microenvironment. G protein-coupled receptors (GPCRs), due to their wide distribution and diverse signaling cascades in tumorigenesis, have emerged as promising targets for CAR-T therapy. This review systematically integrates recent advances of GPCR CAR-T therapy for cancer immunotherapy, with a particular emphasis on current targeting strategies and optimization approaches. This includes the identification of GPCRs as novel tumor-associated antigens to expand CAR-T therapeutic applications, co-expressi on of chemokine receptors to enhance tumor infiltration, and utilization ofGPCR signaling pathways to improve CAR-T cell persistence and cytotoxic efficacy. Potential future research directions include application of AI(Artificial Intelligence) to expedite the development of GPCR antibodies, creation of precision therapies targeting GPCR complexes, modulation of GPCR dimerization networks to maintain homeostasis of membrane antigen expression, employment of nanobody platform to enhance targeting specificity, and design of GPCR allosteric modulators as molecular switches for CAR-T cells. Additionally, this review also examines the application of specific antibodies and other immunotherapeutic approaches of GPCRs in oncology. Overall, this review aims to provide novel scientific and therapeutic perspectives for CAR-T cell therapy in treating mutiple types of human cancers.