Dunderdale Ella M, Abt Evan R
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, United States.
Front Oncol. 2025 May 30;15:1483769. doi: 10.3389/fonc.2025.1483769. eCollection 2025.
Nucleoside metabolism regulates immune cell development and function, but the therapeutic implications of this link have yet to be fully realized. Evidence for the importance of nucleoside metabolism in immune system control was provided by observations of immunodeficiency and autoimmunity across patients with genetic errors that alter nucleoside synthesis or breakdown. Research over the past several decades has uncovered a multifaceted role for nucleosides in mediating immune responses that involves their function as metabolic precursors and as ligands for immune receptors. These findings prompted the development of treatments that block the production of the immunosuppressive nucleoside adenosine for cancer immunotherapy. Guanosine and pyrimidine nucleosides also mediate immune outcomes, and the key regulators of their metabolism are promising new targets to unleash anti-cancer immune responses or dampen autoimmune reactions. This review provides an overview of (i) recent research concerning the mechanisms underlying nucleoside-mediated immune regulation, (ii) the current landscape of therapeutic targets for immune modulation within nucleoside metabolism, and (iii) opportunities for developing improved preclinical models that recapitulate human nucleoside metabolism, which are needed to advance new metabolism-targeting therapies toward the clinic.
核苷代谢调节免疫细胞的发育和功能，但其在治疗方面的潜在应用尚未得到充分认识。通过观察患有改变核苷合成或分解的基因缺陷的患者出现的免疫缺陷和自身免疫现象，证明了核苷代谢在免疫系统调控中的重要性。过去几十年的研究揭示了核苷在介导免疫反应中具有多方面作用，包括作为代谢前体以及作为免疫受体配体的功能。这些发现促使人们开发出在癌症免疫治疗中阻断免疫抑制性核苷腺苷生成的治疗方法。鸟苷和嘧啶核苷也介导免疫反应结果，其代谢的关键调节因子有望成为激发抗癌免疫反应或抑制自身免疫反应的新靶点。本综述概述了：（i）近期关于核苷介导免疫调节机制的研究；（ii）核苷代谢中免疫调节治疗靶点的现状；（iii）开发能够模拟人类核苷代谢的改进临床前模型的机会，这对于推进新的代谢靶向治疗进入临床至关重要。
