Immunomodulatory crosstalk between GPCR and hippo signaling in cancer: implications for tumor immunity and therapeutic targeting.

G protein-coupled receptors (GPCRs) and the Hippo signaling pathway are central regulators of tissue homeostasis, cell proliferation, and immune modulation. Emerging evidence reveals a pivotal, bidirectional crosstalk between these systems in cancer initiation, progression, and immune evasion. This review systematically outlines the molecular mechanisms of GPCR--Hippo interactions, with a particular emphasis on their immunomodulatory functions within the tumor microenvironment (TME). We highlight how distinct G protein subtypes (e.g., Gs vs. G12/13) exert opposing effects on the core Hippo kinase cascade, thereby modulating the activity of the downstream transcriptional co-activators YAP/TAZ. These effectors are key regulators of immune checkpoint expression (e.g., PD-L1), stromal reprogramming, and immune cell recruitment/function. Notably, oncogenic positive-feedback transcriptional loops (e.g., OXTR--YAP, CXCR7--YAP) have been identified as potent self-reinforcing drivers of both malignancy and immunosuppression. Furthermore, biased GPCR signaling and integration with other pathways (e.g., Wnt, TGF-β) form a context-dependent regulatory network that shapes innate and adaptive antitumor immunity. Therapeutically, this axis offers a rich landscape for intervention, including direct YAP/TAZ--TEAD inhibitors, selective GPCR modulators, drug repurposing, and rational combinations with immune checkpoint blockade (ICB). Biomarkers based on GPCR expression, Hippo activity, and immune cell spatial signatures are critical for patient stratification. Future research should leverage single-cell multi-omics, spatial biology, and machine learning to decipher cell-specific signaling within the TME and accelerate the translation of immune-modulating combinatorial therapies.