Protein Lactylation in Cancer: From Mechanisms to Therapy
4 affiliations
- 1Department of Radiation Medicine Faculty of Naval Medicine Naval Medical University Shanghai China
- 2School of Public Health China Medical University Shenyang China
- 3Department of Hepatic Surgery VI Eastern Hepatobiliary Surgery Hospital Naval Medical University Shanghai China
- 4Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices Shanghai China
Abstract
Protein lactylation has emerged as a metabolically responsive posttranslational modification linking lactate accumulation to epigenetic and functional adaptation in cancer. Initially identified on histones, lactylation is now recognized on diverse nonhistone proteins involved in DNA damage repair, immune regulation, redox homeostasis, metabolic remodeling, and cellular plasticity. However, current evidence remains fragmented across treatment modalities, and many reported lactylation events lack site‐specific functional validation and translational assessment. This review addresses this gap by integrating the metabolic and enzymatic basis of protein lactylation with its roles in chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We critically examine how lactylation may promote tumor persistence under therapeutic pressure by enhancing genome maintenance, immune evasion, stress‐survival signaling, metabolic adaptability, and tumor microenvironment remodeling. We also evaluate emerging strategies targeting lactate production and transport, lactylation‐regulating enzymes, and functionally validated substrates, including their potential use in combination therapies. Finally, we discuss major barriers to clinical translation, including incomplete characterization of regulatory enzymes, limitations in site‐specific lactylome mapping, insufficient causal validation, lack of clinically qualified biomarkers, tumor metabolic heterogeneity, and challenges in achieving therapeutic selectivity. Collectively, protein lactylation represents an emerging mechanistic framework for understanding cancer treatment adaptation and a potentially targetable axis whose clinical relevance requires rigorous validation.
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BibTeX
@article{huang2026protein,
title = {{Protein Lactylation in Cancer: From Mechanisms to Therapy}},
author = {Wentian Huang and Ping Hu and Shun Wang and Xide Zhang and Ziran Ye and Shengqiang Chen and Fu Gao and Yuanyuan Chen and Yanyong Yang},
journal = {MedComm},
year = {2026},
month = oct,
doi = {10.1002/mco2.71106},
url = {https://europepmc.org/article/PMC/PMC13722952},
note = {CC BY},
}
RIS
TY - JOUR
TI - Protein Lactylation in Cancer: From Mechanisms to Therapy
AU - Wentian Huang
AU - Ping Hu
AU - Shun Wang
AU - Xide Zhang
AU - Ziran Ye
AU - Shengqiang Chen
AU - Fu Gao
AU - Yuanyuan Chen
AU - Yanyong Yang
PY - 2026
DA - 2026/10/31
JO - MedComm
DO - 10.1002/mco2.71106
UR - https://europepmc.org/article/PMC/PMC13722952
AB - Protein lactylation has emerged as a metabolically responsive posttranslational modification linking lactate accumulation to epigenetic and functional adaptation in cancer. Initially identified on histones, lactylation is now recognized on diverse nonhistone proteins involved in DNA damage repair, immune regulation, redox homeostasis, metabolic remodeling, and cellular plasticity. However, current evidence remains fragmented across treatment modalities, and many reported lactylation events lack site‐specific functional validation and translational assessment. This review addresses this gap by integrating the metabolic and enzymatic basis of protein lactylation with its roles in chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We critically examine how lactylation may promote tumor persistence under therapeutic pressure by enhancing genome maintenance, immune evasion, stress‐survival signaling, metabolic adaptability, and tumor microenvironment remodeling. We also evaluate emerging strategies targeting lactate production and transport, lactylation‐regulating enzymes, and functionally validated substrates, including their potential use in combination therapies. Finally, we discuss major barriers to clinical translation, including incomplete characterization of regulatory enzymes, limitations in site‐specific lactylome mapping, insufficient causal validation, lack of clinically qualified biomarkers, tumor metabolic heterogeneity, and challenges in achieving therapeutic selectivity. Collectively, protein lactylation represents an emerging mechanistic framework for understanding cancer treatment adaptation and a potentially targetable axis whose clinical relevance requires rigorous validation.
SN - 2688-2663
ER -