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To address this, we herein grafted dichloroacetic acid into perylenediimide (PDI) skeleton via ionic or covalent bond to create PDIC\u2010AC and PDIC\u2010NAC. Studies demonstrate that ionic bond\u2010driven primary amine positive nitrogen remodeling and mitochondrial localization endow PDIC\u2010AC with significantly stronger inhibitory activity on pyruvate dehydrogenase kinases (PDHKs) than PDIC\u2010NAC. Notably, PDIC\u2010AC targets the Rieske iron\u2010sulfur polypeptide 1 (UQCRFS1) subunit of complex III in mitochondria, triggering electron leakage from the electron transport chain, thereby more efficiently inducing reactive oxygen species (ROS) production relative to PDIC\u2010NAC. Superior PDHKs inhibiting efficacy and ROS generation capacity functionalize PDIC\u2010AC as an efficient inhibitor to block glycolysis and OXPHOS, which not only repolarize macrophages toward anti\u2010tumor M1 phenotype via suppression of lactate production, but also trigger immunogenic cell death via PERK\u2010eIF2\u03b1\u2010ATF4\u2010CHOP axis to activate immune response, ultimately reaching effective chemo\u2010immunotherapy against the primary and distant tumors. Overall, this work defines the unambiguous mechanism for PDI\u2010triggered endogenous ROS generation, and meanwhile clarifies small\u2010molecule regulators' energy metabolism intervention mechanism and establishes an innovative chemical bond engineering strategy for energy\u2010targeted chemo\u2010immunotherapy.<\/jats:p>","DOI":"10.1002\/advs.77135","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T15:31:45Z","timestamp":1786462305000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chemical Bond\u2010Orchestrated Energy Depletion to Augment Lung Cancer Chemo\u2010Immunotherapy"],"prefix":"10.1002","author":[{"given":"Xuejie","family":"Zhao","sequence":"first","affiliation":[{"name":"Laboratory for NanoMedical Photonics School of Basic Medical Science Henan University  Kaifeng People's Republic of 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