Background: Pancreatic cancer has a high mortality rate worldwide, and is predicted to be third leading cause of death in the near future. However, the regulatory mechanisms that inhibit the progression of pancreatic cancer remain elusive. Currently, exploring the function and mechanisms of GPCRs (G-protein coupled receptors) is an important way to discover promising therapeutic targets for cancer. Methods: GPRC5A expression was measured using real-time quantitative PCR, immunohistochemistry and western blot assays. Cell proliferation and migration were assessed using CCK-8, clone formation, wound-healing and transwell assays. A cytosolic/nuclear distribution experiment was used to detect the protein location transfer. A xenograft model of pancreatic cancer was established to explore the role of GPRC5A in vivo. Results: GPRC5A expression was increased in pancreatic cancer, and disruption of GPRC5A expression inhibited tumor growth in vivo. Mechanistically, GPRC5A positively regulated the transcription of YAP1 through cAMP-CREB signaling. Moreover, we show that the proliferation and migration induced by GPRC5A in pancreatic cancer could be rescued by inhibiting YAP1 expression. Conclusions: GPRC5A interacts with the Hippo pathway to promote the progression of pancreatic cancer. These findings reveal an important crosstalk model and provide potential targets for pancreatic cancer therapy.

G protein‐coupled receptors (GPCRs) are essential contributors to tumor growth and metastasis due to their roles in immune cell regulation. Therefore, GPCRs are potential targets for cancer immunotherapy. Here, we discuss the current understanding of the roles of GPCRs and their signaling pathways in tumor progression from an immunocellular perspective. Additionally, we focus on the roles of GPCRs in regulating immune checkpoint proteins involved in immune evasion. Finally, we review the progress of clinical trials of GPCR‐targeted drugs for cancer treatment, which may be combined with immunotherapy to improve treatment efficacy. This expanded understanding of the role of GPCRs may shed light on the mechanisms underlying tumor progression and provide a novel perspective on cancer immunotherapy.

The targeting of G protein-coupled receptors (GPCRs) has emerged as a promising strategy for developing novel cancer therapies. Moreover, inactivation of the Hippo signaling pathway is recognized as a critical driver of gastric cancer (GC) progression. However, the precise molecular mechanisms underlying cross-talk between GPCRs and the Hippo pathway remain to be further investigated. Here, we identify NPSR1 as an oncogenic driver promoting GC advancement. NPSR1 is significantly overexpressed in GC tissues and negatively correlates with patient prognosis. Both in vivo and in vitro studies demonstrated that NPSR1 overexpression robustly accelerated GC cell proliferation and migration, while its silencing suppressed tumor progression. Mechanistically, our findings revealed a dual regulatory axis: (i) NPSR1 activated the cAMP/CREB pathway to enhance YAP1 transcription; and (ii) it directly facilitated phosphatase PP2Ac expression, thereby reducing YAP1 phosphorylation. This promotes the translocation of YAP1 from the cytoplasm to the nucleus, enhancing its oncogenic function. Our study uncovers a novel molecular link between NPSR1 hyperactivation and Hippo pathway suppression through coordinated transcriptional upregulation and post-translational modulation of YAP1. These results highlight NPSR1 as a potential therapeutic target for GC, offering a rationale for developing targeted inhibitors to restore Hippo signaling.