Is adenosine signalling entering the precision medicine era? From receptor pharmacology to patient stratification.

Over the past three decades, adenosine signalling has emerged as a fundamental regulatory system controlling immune responses, tissue homeostasis, metabolism, and repair processes. The identification of four adenosine receptor subtypes and the development of selective agonists and antagonists generated substantial enthusiasm for therapeutic targeting across a broad spectrum of inflammatory, autoimmune, metabolic, and neoplastic diseases. However, despite compelling preclinical evidence, the clinical translation of adenosine-based therapies has often yielded inconsistent or disappointing results. Increasing evidence suggests that these limitations may not primarily reflect inadequate pharmacological tools, but rather an incomplete understanding of the remarkable spatial, temporal, and cellular heterogeneity of adenosine signalling in human disease. Advances in immunology, systems biology, single-cell technologies, spatial transcriptomics, metabolomics, and artificial intelligence are revealing highly diverse purinergic landscapes across tissues and patient populations. These findings challenge the traditional "one receptor-one disease" paradigm and support a transition toward precision medicine approaches capable of identifying disease-specific and patient-specific purinergic signatures. In this commentary, we discuss how the field is moving beyond classical receptor pharmacology toward biomarker-driven patient stratification. We propose that the next generation of purinergic therapeutics will depend not only on improved drugs but also on the ability to define when, where, and in whom adenosine signalling should be manipulated. Such a shift may ultimately represent the long-awaited bridge between decades of successful experimental research and meaningful clinical implementation.