Spermidine Remodels the Mitochondrial Metabolism of Tumor‐Infiltrating Lymphocytes

Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TILs) has significant potential in treating various cancers; however, its effectiveness is often compromised by the tendency of TILs to become exhausted and dysfunctional. Revitalizing these essential immune cells is crucial for amplifying their antitumor efficacy. Our study investigates the influence of spermidine on the metabolic pathways of TILs, focusing on its critical contribution to T cell vitality. We assessed the impact of spermidine on glucose absorption, mitochondrial functionality, and energy production in TILs. The application of spermidine resulted in a pronounced improvement in mitochondrial functionality and energy production, indicated by a surge in mitochondrial numbers and enhanced activity of the tricarboxylic acid (TCA) cycle. Importantly, the suppression of mitochondrial metabolism negated the beneficial effects of spermidine on mitigating exhaustion and enhancing cellular activity, highlighting the essential role of mitochondrial metabolism in the action of spermidine. Our research suggests that modulation of metabolism by spermidine could be a potential strategy to strengthen the antitumor capabilities of TIL-based treatments, offering a promising method to better manage solid tumors.