Targeting ClpP Rewires the Metabolic-Immune Axis in Acute Myeloid Leukemia

Abstract Acute myeloid leukemia (AML) critically depends on oxidative phosphorylation (OXPHOS). Mitochondrial targeted therapies are advancing into clinical trials, but metabolic vulnerabilities have been primarily explored from a tumor-intrinsic perspective. Leukemic cells can actively reshape an immunosuppressive tumor microenvironment through metabolic competition, highlighting the importance of evaluating the impact of mitochondrial targeted therapies on antitumor immunity. Here, we showed that elevated expression of the mitochondrial caseinolytic protease P (ClpP) is associated with advanced AML. Development of IMP125, a potent ClpP agonist, enabled dual targeting of AML to elicit robust anti-leukemic activity. In addition to direct cytotoxicity, IMP125 induced immunometabolic reprogramming of AML models. Owing to differential ClpP expression, IMP125 preferentially suppressed mitochondrial respiration and oxygen consumption in AML cells while exerting minimal direct effects on T-cell respiration. By reducing AML oxygen consumption and metabolic demand, IMP125 alleviated hypoxia and metabolic competition within the leukemic niche. In this remodeled microenvironment, T cells exhibited recovery of OXPHOS, effector function, and memory-associated features, consistent with an indirect mechanism mediated through metabolic suppression in AML cells. The anti-leukemic efficacy of IMP125 was dependent on T cells and was synergistically enhanced by PD-1 blockade. Collectively, this work reframes ClpP agonism from a tumor-intrinsic therapy to a strategy that actively induces metabolic–immune rewiring, bridging ClpP-targeted and immunotherapeutic approaches for mitochondrial-dependent AML.