Succinate-loaded tumor cell–derived microparticles reprogram tumor-associated macrophage metabolism
Shuya Lu, Jiexiao Li, Yonggang Li, Shichuan Liu, Yutong Liu, Yue Liang, Xifen Zheng, Y. Chen, Jinghui Deng, Huafeng Zhang, Jingwei Ma, Jiadi Lv, Yugang Wang, Bo Huang, Ke Tang
Abstract
The tumor microenvironment predominantly polarizes tumor-associated macrophages (TAMs) toward an M2-like phenotype, thereby inhibiting antitumor immune responses. This process is substantially affected by metabolic reprogramming; however, reeducating TAMs to enhance their antitumor capabilities through metabolic remodeling remains a challenge. Here, we show that tumor-derived microparticles loaded with succinate (SMPs) can remodel the metabolic state of TAMs. SMPs promote classical M1-like polarization of macrophages by enhancing glycolysis and attenuating the tricarboxylic acid (TCA) cycle in a protein succinylation–dependent manner. Mechanistically, succinate is delivered into the mitochondria and nucleus by SMPs, leading to succinylation of isocitrate dehydrogenase 2 (IDH2) and histone H3K122 within the lactate dehydrogenase A ( Ldha ) promoter region. Our findings provide a distinct approach for TAM polarization using cell membrane–derived microparticles loaded with endogenous metabolites, a platform that may be used more broadly for posttranslational modification–based tumor immunotherapy.