Simões Júlia Leão Batista, Bagatini Margarete Dulce
Graduate Program in Biochemistry, Federal University of Santa Catarina (UFSC), Florianópolis 88040-970, SC, Brazil.
Graduate Program in Medical Sciences, Federal University of Fronteira Sul, Chapecó 89815-899, SC, Brazil.
Int J Mol Sci. 2025 Aug 31;26(17):8474. doi: 10.3390/ijms26178474.
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.
甲状腺癌（TC）是最常见的内分泌肿瘤，其发病率呈上升趋势，这凸显了对新治疗方法的需求，尤其是针对放射性碘难治性病例，这些病例通常与 、 、 等基因突变有关。本综述提出了一种机制模型，该模型突出了肿瘤微环境（TME）的两个相互关联的特征：氧化还原失衡和慢性炎症，这是肿瘤进展和治疗耐药性的关键因素。因此，天然酚类化合物，如姜黄素、槲皮素、白藜芦醇和表没食子儿茶素没食子酸酯（EGCG），并非简单地作为抗氧化剂发挥作用，而是作为能够重新编程TME的多效性药物。这些化合物的核心作用机制是调节嘌呤能轴（CD39/CD73/腺苷），这是一个关键的免疫代谢检查点。通过在肿瘤细胞中选择性地诱导致命的氧化应激，抑制促生存的炎症途径，如由核因子κB（NF-κB）介导的途径，并破坏腺苷赋予的免疫抑制屏障，某些植物化学物质显示出恢复免疫监视和促进肿瘤细胞凋亡的潜力。在这种背景下，对与靶向嘌呤能信号相关的证据进行批判性分析变得至关重要，因为对该途径进行药理学增强，尤其是与基于免疫检查点阻断的免疫疗法联合使用时，已成为克服治疗耐药性的一种有前景的策略。
