Lactate‐Driven Restriction of Mitochondrial Permeability Transition Promotes Resistance to Chemo‐Immunotherapy by Suppressing Tumor PANoptosis

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.