Non-histone protein L-lactylation in cancer: a metabolic switch for immune evasion and therapeutic resistance.
5 affiliations
- 1Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- 2Academician (Expert) Workstation of Sichuan Province, Fundamental and Clinical Research on Mental Disorders Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China. [email protected].
- 3Academician (Expert) Workstation of Sichuan Province, Fundamental and Clinical Research on Mental Disorders Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.
- 4Academician (Expert) Workstation of Sichuan Province, Fundamental and Clinical Research on Mental Disorders Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China. [email protected].
- 5Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
Abstract
Initially characterized as an epigenetic marker for transcriptional regulation, lysine lactylation is now recognized as a pervasive posttranslational modification with extensive functions beyond those associated with chromatin. Recent methodological advances in the resolution of stereoisomeric dynamics have established L-lactylation as the predominant glycolysis-derived functional form, providing a metabolic switch that couples glycolytic flux to oncogenic signaling. Here, we provide a comprehensive overview of non-histone L-lactylation in cancer biology. We define the spatially compartmentalized catalytic network governing this process, detailing how nuclear EP300/CBP, cytosolic AARS1, and mitochondrial AARS2 mediate stereospecific targeted modifications. At the molecular level, non-histone L-lactylation alters protein biophysics via charge neutralization, steric hindrance, and interface remodeling. These physicochemical alterations govern fundamental enzymatic kinetics, complex assembly, subcellular trafficking, and proteasomal degradation processes. Through primarily transcription-independent mechanisms, L-lactylation enables cancer cells to sustain metabolic flexibility, promote the repair of damaged DNA, and foster an immunosuppressive tumor microenvironment. Because tumors exploit these regulatory networks to drive adaptive resistance across diverse therapeutic modalities, we examine current strategies for pharmacological intervention. Finally, we highlight critical unresolved questions in this field. Notably, the identification of lactylation-specific readers and the development of stereoisomer-resolved chemobiological tools will be essential to fully leverage this metabolism-modification axis for cancer therapy.
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BibTeX
@article{guo2026nonhistone,
title = {{Non-histone protein L-lactylation in cancer: a metabolic switch for immune evasion and therapeutic resistance.}},
author = {Yingli Guo and Lanyang Gao and Shunda Li and Jicun Chen and Wenguang Fu and Xuelei Ma},
journal = {Molecular cancer},
year = {2026},
month = aug,
doi = {10.1186/s12943-026-02759-7},
url = {https://europepmc.org/article/MED/42958244},
note = {CC BY},
}
RIS
TY - JOUR
TI - Non-histone protein L-lactylation in cancer: a metabolic switch for immune evasion and therapeutic resistance.
AU - Yingli Guo
AU - Lanyang Gao
AU - Shunda Li
AU - Jicun Chen
AU - Wenguang Fu
AU - Xuelei Ma
PY - 2026
DA - 2026/08/01
JO - Molecular cancer
DO - 10.1186/s12943-026-02759-7
UR - https://europepmc.org/article/MED/42958244
AB - Initially characterized as an epigenetic marker for transcriptional regulation, lysine lactylation is now recognized as a pervasive posttranslational modification with extensive functions beyond those associated with chromatin. Recent methodological advances in the resolution of stereoisomeric dynamics have established L-lactylation as the predominant glycolysis-derived functional form, providing a metabolic switch that couples glycolytic flux to oncogenic signaling. Here, we provide a comprehensive overview of non-histone L-lactylation in cancer biology. We define the spatially compartmentalized catalytic network governing this process, detailing how nuclear EP300/CBP, cytosolic AARS1, and mitochondrial AARS2 mediate stereospecific targeted modifications. At the molecular level, non-histone L-lactylation alters protein biophysics via charge neutralization, steric hindrance, and interface remodeling. These physicochemical alterations govern fundamental enzymatic kinetics, complex assembly, subcellular trafficking, and proteasomal degradation processes. Through primarily transcription-independent mechanisms, L-lactylation enables cancer cells to sustain metabolic flexibility, promote the repair of damaged DNA, and foster an immunosuppressive tumor microenvironment. Because tumors exploit these regulatory networks to drive adaptive resistance across diverse therapeutic modalities, we examine current strategies for pharmacological intervention. Finally, we highlight critical unresolved questions in this field. Notably, the identification of lactylation-specific readers and the development of stereoisomer-resolved chemobiological tools will be essential to fully leverage this metabolism-modification axis for cancer therapy.
SN - 1476-4598
ER -