To reprogram M2-like macrophages in the TME and enhance their antitumor efficacy, Lu and Li et al. used electroporation to load tumor cell membrane-derived microparticles with succinate (SMPs), which delivered succinate intracellularly into mitochondria and the nucleus of macrophages. SMPs, but not free succinate, induced succinylation of isocitrate dehydrogenase 2 (promoting HIF-1α stabilization) and histone H3K122 (promoting lactate dehydrogenase A expression), resulting in increased glycolysis, TCA cycle attenuation, and metabolic reprogramming of TAMs into M1 polarized macrophages. SMPs inhibited tumor progression and increased survival in several murine tumor models.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (2) Department of Biochemistry and
Author Info: (1) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (2) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China. (3) Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan 430079, China. (4) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (5) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (6) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (7) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (8) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (9) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (10) Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (11) Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (12) Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China. (13) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan 430030, China. (14) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China. (15) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China. Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan 430030, China.
