脂多糖曝露诱导巨噬细胞进行代谢重编程伴随着促炎性极化，表现为有氧糖酵解升高以及三羧酸循环受阻。然而，与脂多糖相比，CD40信号可以通过一些尚未定义的代谢重编程来驱动促炎性和抗肿瘤极化。在这里，我们展示了CD40的激活触发脂肪酸氧化和谷氨酰胺代谢，促进ATP柠檬酸裂解酶依赖的促炎基因和抗肿瘤表型的表观遗传重编程。机制上，谷氨酰胺的使用通过谷氨酰胺转乳酸的转化微调了NAD+/NADH比例，加强了脂肪酸氧化诱导的促炎和抗肿瘤活化。在参与CD40介导的代谢重编程的重要代谢酶基因消融的情况下，对抗CD40介导的抗肿瘤反应以及重新教育肿瘤相关巨噬细胞的影响消失。综上所述，这些数据表明代谢重编程，包括脂肪酸氧化和谷氨酰胺代谢，控制促炎性和抗肿瘤极化的活化，并强调了肿瘤相关巨噬细胞在接受CD40激动剂治疗之前代谢预处理的治疗潜力。 ©2023. 作者。

Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD+/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments.© 2023. The Author(s).