Targeting the Purinergic Axis with Phenolic Compounds to Disrupt the Oxidative-Inflammatory Cycle in Thyroid Cancer.

Thyroid cancer (TC), the most prevalent endocrine neoplasia, has shown a progressive incidence, highlighting the need for new therapeutic approaches-especially for radioiodine-refractory cases, often associated with mutations in genes such as , , and . This review proposes a mechanistic model that highlights two interrelated characteristics of the tumor microenvironment (TME): redox imbalance and chronic inflammation, key elements in tumor progression and treatment resistance. Thus, natural phenolic compounds, such as curcumin, quercetin, resveratrol, and epigallocatechin gallate (EGCG), function not as simple antioxidants but as pleiotropic agents that reprogram the TME. A central mechanism of action for these compounds is the modulation of the purinergic axis (CD39/CD73/adenosine), a critical immune-metabolic checkpoint. By selectively inducing lethal oxidative stress in tumor cells, suppressing pro-survival inflammatory pathways-such as that mediated by nuclear factor kappa B (NF-κB)-and destabilizing the immunosuppressive shield conferred by adenosine, certain phytochemicals demonstrate the potential to restore immune surveillance and promote tumor apoptosis. In this context, a critical analysis of the evidence related to targeting purinergic signals becomes essential, since pharmacological reinforcement of this pathway, especially when combined with immunotherapies based on immune checkpoint blockade, emerges as a promising strategy for overcoming therapeutic resistance.