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journal article·2026-06-30Open access

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

Sen Zhong, Wenlong Chen, Fanglong Liu, Shengyi Zhou, Bolin Yu, Yuying Wang, Xiqian Zhou, Xuehui Wang, Diya Liu, Zhuoyu Zhang, Xinran Wang, Mounia Lalouly, Yiwen Li, Zhefei Du, Tao Yan, Zhihui Xiao, Zhou Zhou, Huanhuan Zhu, Fengyuan Qian, Bowen Zheng, Lin Fang

Advanced Science
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Abstract

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.
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Research context

Catalysis & surfaces

OpenAlex topics: Cancer, Hypoxia, and Metabolism · Mitochondrial Function and Pathology · Ferroptosis and cancer prognosis

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

School of Medicine Shanghai Tenth People's Hospital Department of Breast and Thyroid Surgery Tongji University Shanghai P. R. China

Department of Thyroid and Breast Surgery Shanghai Tenth People's Hospital Clinical Medical College of Nanjing Medical University Shanghai P. R. China

Department of Breast Surgery Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai P. R. China

Department of Breast Surgery The First Affiliated Hospital of Anhui University of Science and Technology Huainan P. R. China

Division of Spine Department of Orthopedics Tongji Hospital affiliated to Tongji University School of Medicine Shanghai P. R. China

Ministry of Education Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University) Shanghai P. R. China

Translational Research Institute of Brain and Brain‐Like Intelligence Shanghai Fourth People's Hospital, and Cancer Center School of Medicine Tongji University Shanghai P. R. China

Department of Breast Surgery Zhejiang Cancer Hospital Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang P. R. China

Wenzhou Medical University Wenzhou Zhejiang P. R. China

Funding

National Natural Science Foundation of China

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