P2Y2 signaling in cancer: mechanisms, biomarkers, and therapeutic horizons

Purinergic P2 receptors have long been attractive therapeutic targets, as evidenced by the clinical success of P2Y12 and P2X3 receptor antagonists. However, P2Y2 receptor remains underexplored in oncology, despite its emerging role in cancer biology and its established clinical utility as the target of the agonist diquafosol for dry eye disease. P2Y2, a G protein-coupled receptor that is activated by extracellular ATP and UTP, integrates multiple oncogenic signaling pathways to drive proliferation, epithelial–mesenchymal transition, invasion, metastasis, and drug resistance. Mechanistically, these effects are mediated through crosstalk with key signaling axes, including EGFR, MAPK, PI3K–AKT, β-catenin, integrins, and HIF-1α. Beyond cancer cell-intrinsic programs, P2Y2 also remodels the tumor microenvironment by promoting angiogenesis, inflammation, and immune evasion, thereby accelerating disease progression. Conversely, P2Y2 activation can induce apoptosis in certain contexts, highlighting its context-dependent, bidirectional role. This review synthesizes current knowledge of P2Y2 structure, signaling mechanisms, and cancer-relevant functions, and surveys advances in pharmacological modulation, including agonists, antagonists, gene-directed strategies, and emerging antibody-based approaches. This review also discusses bioinformatic evidence supporting P2Y2 as a potential biomarker and outlines future directions integrating structural biology and digital medicine to advance P2Y2-targeted precision oncology. • P2Y2 integrates ATP/UTP signals to regulate major oncogenic pathways. • P2Y2 drives EMT, metastasis, therapy resistance, and immune suppression. • Context‑dependent P2Y2 signaling can promote tumor growth or apoptosis. • Targeting P2Y2 reshapes the tumor microenvironment and restores therapy response. • P2Y2 shows promise as a biomarker and a precision oncology target.