肿瘤内不变自然杀伤T（iNKT）细胞的功能障碍阻碍了其抗肿瘤功效，但其潜在机制以及与内源性抗原引发的关系仍有待探索。在此，我们报告抗原引发导致代谢重编程和表观遗传重塑，从而导致 iNKT 细胞功能重编程，其特征是再刺激时细胞因子反应有限，但具有高细胞毒性。从机制上讲，抗原引发的 iNKT 细胞中氧化磷酸化 (OXPHOS) 受损会在通过减少 mTORC1 激活进行再刺激时抑制 TCR 信号传导以及糖酵解升高，从而导致细胞因子产生受损。然而，抗原引发的 iNKT 细胞中的代谢重编程与其增强的细胞毒性无关。相反，表观遗传重塑解释了它们的颗粒酶的高表达。值得注意的是，由于肿瘤中的内源抗原引发，瘤内 iNKT 细胞与抗原引发的 iNKT 细胞具有相似的代谢重编程和功能重编程，因此 ZLN005 恢复瘤内 iNKT 细胞中的 OXPHOS 成功增强了其抗肿瘤反应。我们的研究破译了抗原引发诱导的代谢重编程和表观遗传重塑对瘤内 iNKT 细胞功能的影响，并提出了一种通过靶向细胞代谢来增强基于 iNKT 细胞的抗肿瘤免疫治疗疗效的方法。

Dysfunction of intratumoral invariant natural killer T (iNKT) cells hinders their anti-tumor efficacy, but the underlying mechanisms and the relationship with endogenous antigen priming remain to be explored. Here, we report that antigen priming leads to metabolic reprogramming and epigenetic remodeling, which causes functional reprogramming in iNKT cells, characterized by limited cytokine responses upon restimulation but constitutive high cytotoxicity. Mechanistically, impaired oxidative phosphorylation (OXPHOS) in antigen-primed iNKT cells inhibited TCR signaling, as well as elevation of glycolysis, upon restimulation via reducing mTORC1 activation, and thus led to impaired cytokine production. However, the metabolic reprogramming in antigen-primed iNKT cells was uncoupled with their enhanced cytotoxicity; instead, epigenetic remodeling explained their high expression of granzymes. Notably, intratumoral iNKT cells shared similar metabolic reprogramming and functional reprogramming with antigen-primed iNKT cells due to endogenous antigen priming in tumors, and thus recovery of OXPHOS in intratumoral iNKT cells by ZLN005 successfully enhanced their anti-tumor responses. Our study deciphers the influences of antigen priming-induced metabolic reprogramming and epigenetic remodeling on functionality of intratumoral iNKT cells, and proposes a way to enhance efficacy of iNKT cell-based anti-tumor immunotherapy by targeting cellular metabolism.