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ABSTRACT Intrinsic resistance limits chemo‐immunotherapy efficacy in triple‐negative breast cancer (TNBC). While metabolic reprogramming is linked to immune evasion, the precise mechanistic orchestration remains unclear. Here, utilizing single‐cell transcriptomics and quantitative lactylome profiling, we show that elevated tumor lactate drives resistance by broadly suppressing PANoptosis. Mechanistically, under chemotherapeutic stress, the Lysine acetyltransferase 8 (KAT8) catalyzes the specific lactylation of the inner mitochondrial membrane ADP/ATP translocator 2 (ANT2) at K92. Lactylated ANT2 recruits the phosphoglycerate mutase 5 (PGAM5) to dephosphorylate Cyclophilin D (CypD). This cascade restricts mitochondrial permeability transition pore (mPTP) opening, preserving mitochondrial homeostasis and averting immunogenic cell death. Crucially, a cell‐penetrating competitive peptide targeting the KAT8‐ANT2 interface effectively uncouples this metabolic lock, re‐sensitizing TNBC tumors to cytotoxic stress and restoring chemo‐immunotherapy efficacy in vivo. Our findings unveil a profound mechanistic link between the Warburg effect and mitochondrial homeostasis, establishing KAT8‐mediated ANT2 lactylation as a targetable vulnerability to improve chemo‐immunotherapy efficacy.
Zhong et al. (Tue,) studied this question.