Systemic purinergic dysregulation in melanoma revealed by soluble P2X4 receptor fragments

Melanoma progression involves coordinated immune suppression, altered receptor-mediated signalling, and tumour-driven metabolic reprogramming. To evaluate these systemic alterations, we integrated three datasets: flow-cytometric profiling of immune cell subsets and P2X4 expression in peripheral blood leukocytes from melanoma patients and healthy controls; molecular detection of P2X4 in plasma, leukocytes, and urine using Western blotting and immunoprecipitation; and NMR-based metabolomic profiling of serum and saliva. Melanoma patients exhibited reduced CD4⁺ T-helper cells, altered Tc/Treg balance, and eosinophil heterogeneity with elevated P2X4 expression. Truncated P2X4 receptor fragments were detected in plasma and urine of some melanoma patients but not in controls. Metabolomic analyses revealed tumour-associated metabolic shifts, including elevated branched-chain amino acids in both serum and saliva and many alterations associated with dysbiosis were detected in melanoma patients’ saliva. These findings highlight the convergence of immune dysregulation, purinergic P2X4 signalling, and systemic metabolic remodelling in melanoma. The presence of soluble P2X4 fragments, together with metabolomic fingerprints, supports their potential as minimally invasive biomarkers for disease monitoring.