近年来，细胞生物能在调控免疫细胞功能和命运方面的核心作用被认识到，引发了对免疫代谢的兴趣，这是一个专注于代谢调控和免疫功能之间相互作用的研究领域。因此，不同刺激条件下，极化为促炎细胞或促解决细胞的巨噬细胞的早期代谢变化已被表征。肿瘤相关巨噬细胞是肿瘤微环境中最常见的细胞之一；然而，对化疗药物对巨噬细胞免疫代谢的影响尚未得到满足的研究。在此，我们采用了系统生物学方法，将转录组学和代谢组学相结合，揭示了两种具有已证实抗肿瘤活性的DNA结合剂trabectedin (TRB)和lurbinectedin (LUR)对免疫炎细胞的免疫代谢效应。我们的结果表明，TRB和LUR通过诱导特定的代谢重组程序（包括ROS产生、线粒体内膜电位变化、磷酸戊糖途径增加、乳酸释放、三羧酸循环、丝氨酸和甲基乙二醛途径）使人体巨噬细胞向促炎性表型活化。谷氨酰胺、天冬氨酸、组氨酸和脯氨酸细胞内水平也减少，而氧耗减少。观察到的免疫代谢变化解释了这些化合物的其他抗肿瘤活性，并为设计特异性靶向免疫代谢景观的治疗干预提供了新的途径。版权 © 2023 Povo-Retana, Fariñas, Landauro-Vera, Mojena, Alvarez-Lucena, Fernández-Moreno, Castrillo, de la Rosa Medina, Sánchez-García, Foguet, Mas, Marin, Cascante and Boscá.

In recent years, the central role of cell bioenergetics in regulating immune cell function and fate has been recognized, giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Thus, early metabolic changes associated with the polarization of macrophages into pro-inflammatory or pro-resolving cells under different stimuli have been characterized. Tumor-associated macrophages are among the most abundant cells in the tumor microenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, we use a systems biology approach that integrates transcriptomics and metabolomics to unveil the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two DNA-binding agents with proven antitumor activity. Our results show that TRB and LUR activate human macrophages toward a pro-inflammatory phenotype by inducing a specific metabolic rewiring program that includes ROS production, changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, lactate release, tricarboxylic acids (TCA) cycle, serine and methylglyoxal pathways in human macrophages. Glutamine, aspartate, histidine, and proline intracellular levels are also decreased, whereas oxygen consumption is reduced. The observed immunometabolic changes explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer.Copyright © 2023 Povo-Retana, Fariñas, Landauro-Vera, Mojena, Alvarez-Lucena, Fernández-Moreno, Castrillo, de la Rosa Medina, Sánchez-García, Foguet, Mas, Marin, Cascante and Boscá.