Chemical Bond‐Orchestrated Energy Depletion to Augment Lung Cancer Chemo‐Immunotherapy

ABSTRACT

Concurrent blockade of aerobic glycolysis and oxidative phosphorylation (OXPHOS) holds great promise in lung cancer therapy yet challenged by tumor cell metabolic plasticity. To address this, we herein grafted dichloroacetic acid into perylenediimide (PDI) skeleton via ionic or covalent bond to create PDIC‐AC and PDIC‐NAC. Studies demonstrate that ionic bond‐driven primary amine positive nitrogen remodeling and mitochondrial localization endow PDIC‐AC with significantly stronger inhibitory activity on pyruvate dehydrogenase kinases (PDHKs) than PDIC‐NAC. Notably, PDIC‐AC targets the Rieske iron‐sulfur 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‐NAC. Superior PDHKs inhibiting efficacy and ROS generation capacity functionalize PDIC‐AC as an efficient inhibitor to block glycolysis and OXPHOS, which not only repolarize macrophages toward anti‐tumor M1 phenotype via suppression of lactate production, but also trigger immunogenic cell death via PERK‐eIF2α‐ATF4‐CHOP axis to activate immune response, ultimately reaching effective chemo‐immunotherapy against the primary and distant tumors. Overall, this work defines the unambiguous mechanism for PDI‐triggered endogenous ROS generation, and meanwhile clarifies small‐molecule regulators' energy metabolism intervention mechanism and establishes an innovative chemical bond engineering strategy for energy‐targeted chemo‐immunotherapy.