Targeting tumor-associated G-protein coupled receptors: beyond single-axis inhibition toward multidimensional regulation

G protein-coupled receptors (GPCRs) serve as central hubs in tumor signal transduction and microenvironment regulation. However, their therapeutic exploitation is confounded by a fundamental complexity: GPCR functions are exquisitely context-dependent, varying across cell types and spatial locations within the heterogeneous tumor microenvironment. A single receptor may drive malignant proliferation while simultaneously recruiting immunosuppressive cells, and pathways inhibited by small molecules can be reactivated through parallel axes. This multidimensional regulatory conundrum renders conventional single-axis inhibition strategies inherently limited. This review systematically examines the distribution and pathological functions of tumor-associated GPCRs, critically analyze why current mainstream modalities often fail in the TME context, and spotlight next-generation strategies such as allosteric modulation, targeted protein degradation, nucleic acid therapeutics, and engineered cell therapies that are uniquely poised to actively modulate the TME in a context-aware manner. By integrating enabling technologies including artificial intelligence, cryo-electron microscopy, and organoid models, we chart a transformative path from single-axis inhibition toward multi-dimensional regulation, ultimately advancing more durable cancer therapies.