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While metabolic reprogramming is linked to immune evasion, the precise mechanistic orchestration remains unclear. Here, utilizing single\u2010cell 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)\u00a0at K92. Lactylated ANT2 recruits the phosphoglycerate mutase 5\u00a0(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\u2010penetrating competitive peptide targeting the KAT8\u2010ANT2 interface effectively uncouples this metabolic lock, re\u2010sensitizing TNBC tumors to cytotoxic stress and restoring chemo\u2010immunotherapy efficacy in vivo. Our findings unveil a profound mechanistic link between the Warburg effect and mitochondrial homeostasis, establishing KAT8\u2010mediated ANT2 lactylation as a targetable vulnerability to improve chemo\u2010immunotherapy efficacy.<\/jats:p>","DOI":"10.1002\/advs.76321","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T22:19:34Z","timestamp":1782857974000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lactate\u2010Driven Restriction of Mitochondrial Permeability Transition Promotes Resistance to Chemo\u2010Immunotherapy by Suppressing Tumor PANoptosis"],"prefix":"10.1002","volume":"13","author":[{"given":"Sen","family":"Zhong","sequence":"first","affiliation":[{"name":"School of Medicine Shanghai Tenth People's Hospital Department of Breast and Thyroid Surgery Tongji University  Shanghai P. R. 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