Inflammation, oxidative stress and purinergic signaling in pituitary neuroendocrine tumors (PitNETs).

Abstract

Pituitary neuroendocrine tumors (PitNETs) constitute a heterogeneous group of intracranial neoplasms with variable biological behavior, whose aggressiveness cannot be explained solely by the intrinsic characteristics of tumor cells. Growing evidence demonstrates that chronic inflammation of the tumor microenvironment (TME) plays a central role in the progression, invasiveness, therapeutic resistance, and recurrence of these tumors. In this context, the purinergic system emerges as a fundamental regulatory axis of the local inflammatory response, integrating signals derived from cellular stress, hypoxia, and metabolic reprogramming. The extracellular release of ATP under conditions of oxidative stress, tissue damage, and cell death serves as a pro-inflammatory signal by activating P2 purinergic receptors. On the other hand, its conversion to adenosine by the ectonucleotidases CD39 and CD73 promotes an immunosuppressive environment, mainly through P1 receptors, such as A2A and A2B. This dynamic balance modulates the infiltration and polarization of immune cells, the production of inflammatory cytokines, including IL-6, IL-8, and TNF-α, the activation of transcriptional pathways such as NF-κB, STAT3, and HIF-1α, and extracellular matrix remodeling and angiogenesis. This study aims to review the role of inflammation in the tumor microenvironment of PitNETs, with emphasis on purinergic signaling as an integrating link between oxidative stress, immune dysfunction, and metabolic reprogramming. Although not abundantly explored, the purinergic pathway in PitNETs shows promising potential: it interconnects different elements of the TME, contributes to tumor mechanisms, and is a potential target for immunomodulatory and anti-inflammatory therapies in pituitary tumors.