Succinate-loaded tumor cell–derived microparticles reprogram tumor-associated macrophage metabolism
Menée à l'aide de modèles murins de tumeur, cette étude met en évidence l'intérêt de microparticules dérivées de tumeurs et chargées en succinate pour modifier le métabolisme des macrophages et améliorer leurs capacités antitumorales en induisant la conversion du phénotype M2 en phénotype M1
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. Engineered tumor cell–derived microparticles induce histone and enzyme succinylation in tumor-associated macrophages to promote an M1-like phenotype. Tumor-associated macrophages (TAMs) are known to suppress antitumor immunity and counter the efficacy of immunotherapies. Here, Lu et al. developed a strategy to specifically repolarize TAMs from a protumoral phenotype into an antitumor one. The authors used tumor-derived microparticles to deliver succinate to the cytoplasm of TAMs. These microparticles, termed SMPs, repolarized TAMs through both epigenetic and metabolic reprogramming and resulted in improved control of tumors in multiple mouse models. Together, these data highlight the potential for targeted TAM reprogramming as a tool in the immunotherapy toolbox. —Courtney Malo
Science Translational Medicine , résumé, 2025