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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\u2013dependent 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 (\n                    <jats:italic>Ldha<\/jats:italic>\n                    ) promoter region. Our findings provide a distinct approach for TAM polarization using cell membrane\u2013derived microparticles loaded with endogenous metabolites, a platform that may be used more broadly for posttranslational modification\u2013based tumor immunotherapy.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adr4458","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T14:00:46Z","timestamp":1744207246000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":67,"title":["Succinate-loaded tumor cell\u2013derived microparticles reprogram tumor-associated macrophage metabolism"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7295-3520","authenticated-orcid":true,"given":"Shuya","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1363-5502","authenticated-orcid":true,"given":"Jiexiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."},{"name":"Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Li","sequence":"additional","affiliation":[{"name":"Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan 430079, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shichuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7999-5608","authenticated-orcid":true,"given":"Yue","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8651-6360","authenticated-orcid":true,"given":"Xifen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghui","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9285-2478","authenticated-orcid":true,"given":"Huafeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3223-6053","authenticated-orcid":true,"given":"Jiadi","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Immunology &amp; State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) &amp; Peking Union Medical College, Beijing 100005, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4687-4742","authenticated-orcid":true,"given":"Yugang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."},{"name":"Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan 430030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8476-1138","authenticated-orcid":true,"given":"Bo","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China."},{"name":"Department of Immunology &amp; 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