Creatine Supplementation in Preclinical Models Receiving Immune Checkpoint Inhibitor Therapy: A Systematic Review

Creatine supplementation is widely used for its ergogenic benefits but has recently garnered interest for its immunomodulatory properties, particularly its capacity to enhance CD8+ T-cell bioenergetics through SLC6A8-mediated transport and phosphocreatine-dependent ATP (adenosine triphosphate) buffering. Emerging preclinical evidence suggests that creatine may potentiate antitumor immunity and augment the efficacy of immune checkpoint inhibitor (ICI) therapies. Conflicting reports of creatine-associated metastasis in select tumor models have raised uncertainty regarding its role in oncologic settings. This review synthesizes current preclinical evidence to assess whether creatine exerts beneficial, neutral, or detrimental effects across experimental oncologic models treated with immune checkpoint therapy. A total of 230 articles were screened, and 5 studies were included within this systematic review. Current preclinical evidence suggests that creatine supplementation may exert beneficial immunomodulatory and antitumor effects when combined with PD-1 blockade, largely by enhancing T-cell metabolic fitness and macrophage-driven inflammatory responses. However, the potential for metastasis in select tumor types poses a risk to the administration of a creatine supplement. This systematic review emphasizes the absence of human data, highlighting a critical knowledge gap. Rigorous mechanistic studies and early-phase clinical trials are essential to determine whether creatine can be safely and effectively integrated into ICI-based treatment strategies.