Creatine metabolic network and host immune interplay: from molecular mechanisms to regulatory strategies

Emerging evidence indicates that creatine, long recognized as an energy buffer in muscle and neural tissues, also plays a critical role in immunometabolic regulation. Research on creatine metabolism and immune regulation spans multiple disciplines, yet a systematic theoretical framework remains lacking. Accordingly, this review proposes a three-dimensional framework of “creatine metabolic flux, immune cell subtype specificity, and microenvironmental regulation”. Beginning with the molecular basis of the creatine metabolic network, we delineate the tissue distribution and functional characteristics of creatine de novo synthesis, transmembrane transport, and the phosphocreatine shuttle. We then analyze, across adaptive immunity, innate immunity, and neuroimmunity, the differential regulatory roles of creatine metabolism in processes including CD8+ T cell antitumor immunity, macrophage polarization, NK cell cytotoxicity, and inflammasome activation. Subsequently, we examine the bidirectional regulatory features of creatine metabolism in the tumor microenvironment and inflammatory microenvironment. Additionally, we synthesize recent advances in creatine metabolism related to anti-infective immunity, vaccine responses, and autoimmune diseases. Throughout, we distinguish direct experimental evidence from correlative observations and explicitly identify the inferential steps that remain to be validated. Through this review, we aim to facilitate a comprehensive understanding of the molecular mechanisms linking creatine metabolism and immune regulation, thereby providing new perspectives for the clinical translation of creatine-based interventions.