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Updated: Jul 2, 2026

Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
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Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer

Published on: January 17, 2025

Lactate-Driven Restriction of Mitochondrial Permeability Transition Promotes Resistance to Chemo-Immunotherapy by

Sen Zhong1, Wenlong Chen1, Fanglong Liu2

  • 1School of Medicine, Shanghai Tenth People's Hospital, Department of Breast and Thyroid Surgery, Tongji University, Shanghai, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 30, 2026
PubMed

Insights

Elevated tumor lactate in triple-negative breast cancer (TNBC) promotes chemo-immunotherapy resistance by suppressing PANoptosis. Targeting KAT8-ANT2 lactylation restores sensitivity, offering a new therapeutic strategy for TNBC.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Immunology

Background:

  • Intrinsic resistance to chemo-immunotherapy poses a significant challenge in treating triple-negative breast cancer (TNBC).
  • Metabolic reprogramming, particularly the Warburg effect, is implicated in immune evasion, but the underlying mechanisms remain elusive.
  • Understanding these mechanisms is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To elucidate the mechanistic link between tumor lactate, metabolic reprogramming, and chemo-immunotherapy resistance in TNBC.
  • To identify specific molecular targets that mediate this resistance.
  • To evaluate a novel therapeutic peptide for overcoming resistance in TNBC.

Main Methods:

  • Single-cell transcriptomics and quantitative lactylome profiling were employed to analyze tumor samples.
  • Investigated the role of Lysine acetyltransferase 8 (KAT8) in catalyzing ANT2 lactylation under chemotherapeutic stress.
  • Assessed the impact of a KAT8-ANT2 interface targeting peptide on TNBC response to chemo-immunotherapy in vivo.

Main Results:

  • Elevated tumor lactate was found to suppress PANoptosis, a key cell death pathway, contributing to chemo-immunotherapy resistance.
  • KAT8-mediated lactylation of ANT2 at K92 was identified as a critical step, recruiting PGAM5 to inhibit mPTP opening and preserve mitochondrial homeostasis.
  • A cell-penetrating peptide targeting the KAT8-ANT2 interface successfully reversed this metabolic lock, restoring sensitivity to chemo-immunotherapy in preclinical models.

Conclusions:

  • Tumor lactate-driven KAT8-mediated ANT2 lactylation represents a novel mechanism of chemo-immunotherapy resistance in TNBC.
  • This metabolic pathway is a targetable vulnerability for improving treatment efficacy.
  • Interfering with ANT2 lactylation offers a promising strategy to re-sensitize TNBC to chemo-immunotherapy.
Keywords:
PANoptosischemo‐immunotherapy resistancelactate metabolismlactylationmitochondrial permeability transition

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