Lactylation as a cross-regulatory node in tumor metabolism and epigenetics: insights and therapeutic implications

Sep 24, 2026

Lactylation is a pivotal cross-regulatory mechanism linking tumor metabolic reprogramming with epigenetic regulation. This review summarizes lactylation writers, erasers, and readers, and delineates tumor-specific functions, especially in remodeling the immunosuppressive tumor microenvironment and driving therapeutic resistance. Mechanistic evidence highlights lactylation as a conduit translating metabolic status into heritable gene-expression programs. Emerging targeting strategies combining metabolic inhibition, epigenetic modulation, and immunotherapy show strong preclinical promise for clinical translation.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

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Introduction

Molecular mechanisms and regulatory networks of lactylation

Catalytic and reverse mechanisms of lactylation

TYPE Review PUBLISHED 25 September 2025 DOI 10.3389/fimmu.2025.1675480 OPEN ACCESS EDITED BY Keqiang Chen, National Cancer Institute at Frederick (NIH), United States REVIEWED BY Ruoxi Yuan, Hospital for Special Surgery, United States Amit Kumar Singh, National Cancer Institute at Frederick (NIH), United States *CORRESPONDENCE Junna Jiao [jiaonajd@163.com](jiaonajd@163.com) RECEIVED 29 July 2025 ACCEPTED 04 September 2025 PUBLISHED 25 September 2025 CITATION Lv Z, Yang R, Liu L, Shi X, Wang R, Wu J and Jiao J (2025) Lactylation as a cross-regulatory node in tumor metabolism and epigenetics: insights and therapeutic implications. Front. Immunol. 16:1675480 . doi: 10.3389/fimmu.2025.1675480 COPYRIGHT © 2025 Lv, Yang, Liu, Shi, Wang, Wu and Jiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Lactylation as a cross-regulatory node in tumor metabolism and epigenetics: insights and therapeutic implications Zhuangwei Lv 1, Ruohao Yang2, Lulu Liu 3, Xiaoyu Shi 3, Ruihan Wang 3, Jinhua Wu 2 and Junna Jiao 2,4* 1School of Forensic Medicine, Xinxiang Medical University, Xinxiang, China, 2School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China, 3School of Junji College, Xinxiang Medical University, Xinxiang, Henan, China, 4Xinxiang Engineering Technology Research Center of Immune Checkpoint Drugs for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, China Lactylation serves as a pivotal cross-regulatory mechanism linking tumor metabolic reprogramming and epigenetic regulation . This review comprehensively summarizes the mechanisms of lactylation writers, erasers, and readers, highlighting their tumor-spec iﬁc functions, roles in immunosuppress ive tumor microenvironment (TME) remodeling, and contributions to therapeutic resistance . Emerging targeting strategies, including metabolic inhibitors, epigenetic modulators, and combination immunotherapies, exhibit promising preclinical efﬁcacy, highlighting their potential for clinical translation in overcoming therapy resistance and improving cancer immunotherapy. KEYWORDS lactylation, metabolic reprogramming, epigenetic regulation, Warburg effect, therapeutic 1 Introduction The crosstalk between tumor metabolic reprogramming and epigenetic regulation represents a core focus in contemporary cancer research. The landmark discovery oflysine lactylation (Kla) in 2019 provided a breakthrough in this ﬁeld, revealing a direct molecular link between lactic acid—a classic end-product of glycolysis—and the regulation of gene expression (1–7) . Previously regarded primarily as a metabolic waste product, lactic acid, through lactylation modiﬁcation, has emerged as a key molecule connecting aberrant tumor metabolism to epigenetic remodeling (8) . This post-translational modiﬁcation plays a central role in tumorigenesis, progression, immune evasion, and therapeutic resistance by transducing cellular metabolic status into heritable gene expression patterns (1, 9–13) . Accumulating evidence conﬁrms that lactylation is abnormally activated across diverse tumor types, with its levels closely correlating with tumor malignancy, patient prognosis, and therapeutic response (14) . Mechanistically, lactylation regulates downstream target Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) gene transcription via histone modiﬁcation or alters protein function through non-histone modiﬁcation, thereby participating in critical biological processes such as tumor cell proliferation, apoptosis, invasion, and metastasis

FAQs

What role does lactylation play in connecting tumor metabolism and epigenetic regulation?

Lactylation directly links metabolic status to gene expression and protein function by coupling lactic acid–derived lactyl groups to lysine residues, thereby influencing tumorigenesis and immune evasion.

How does the tumor microenvironment affect lactylation in immune cells?

Accumulated lactic acid in the tumor microenvironment induces lactylation in immune cells, reshaping an immunosuppressive tumor microenvironment and promoting immune evasion.

What therapeutic strategies are discussed to target lactylation?

The review highlights emerging strategies including metabolic inhibitors, epigenetic modulators, and combination immunotherapies aimed at overcoming therapy resistance and improving cancer immunotherapy outcomes.

Sep 24, 2026

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