Editorial: Therapy resistance in tumor microenvironment: metabolic reprogramming and purinergic signaling

Fundamental pathophysiological processes such as tissue homeostasis, neurodegeneration, immunity, inflammation, and cancer are modulated by purinergic signaling (1). The tumor microenvironment (TME) is enriched in nucleosides and nucleotides, and its cellular and biochemical composition affects tumor progression, metastatic spread, and response to therapy (2). Current therapeutic approaches such as surgery, chemotherapy, targeted therapy, hormonal therapy, radiotherapy, and immunotherapy can profoundly alter TME composition, causing extensive cell death, activating the immune system, and provoking a massive release of inflammatory and damage-associated molecular patterns (DAMPS), including nucleotides (ATP and ADP) and nucleosides (adenosine) (3). The impact of these purines on TME strictly depends on the repertoire of P1 (also known as A receptors or ADORA) and P2 receptors and ectonucleotidases (CD39 and CD73) expressed by tumor, immune, and stromal cells, affecting cancer proliferation and several metabolic pathways and promoting both immunostimulatory (eATP) or immunosuppressive (adenosine) responses (2, 4). This Research Topic includes two reviews and three research articles that discuss the role of purinergic signaling in the context of tumor progression and resistance to therapies, also proposing the purinergic axis as a novel therapeutic target in cancer.