# Protein Lactylation in Cancer: Mechanisms and Therapeutic Targets

## TL;DR

This paper reviews how lactate, a byproduct of cancer metabolism, modifies proteins through lactylation and influences cancer progression and treatment resistance.

## Contribution

The paper introduces lactylation as a novel metabolic-epigenetic axis for precision oncology and potential therapeutic targeting.

## Key findings

- Lactylation links glycolytic metabolism to epigenetic and proteomic changes in cancer cells.
- Lactylation affects chemotherapy, targeted therapy, and immunotherapy responses by modifying DNA repair and signaling proteins.
- Lactylation contributes to an immunosuppressive tumor microenvironment and therapy resistance.

## Abstract

The Warburg effect states that cancer cells preferentially undergo aerobic glycolysis, producing lactate as a key metabolic byproduct. Lactate acidifies the tumor microenvironment (TME) and serves as a signaling molecule and substrate for lysine lactylation (Kla), a novel posttranslational modification (PTM) discovered in 2019 that links glycolytic metabolism to epigenetic and proteomic reprogramming. The reversible modification of histones and nonhistone proteins orchestrates oncogenic adaptation and drives tumor progression. However, gaps persist in our understanding of the multifactorial regulation of lactylation and its translational potential in overcoming tumor heterogeneity and resistance. This review highlights the emerging roles of lactylation in cancer therapies, including the enhancement of DNA repair mechanisms during chemotherapy, stabilization of key signaling effectors upon targeted therapy, and promotion of an immunosuppressive TME in immunotherapy. We further examined regulatory factors associated with lactylation, from competitive PTMs and genetic mutations to microbial influences and environmental signals. Additionally, we discuss the therapeutic potential of targeting lactylation via indirect modulators currently under investigation and the visualization of lactate and lactylation modifications. By synthesizing these insights, this review highlights lactylation as a reversible metabolic‐epigenetic axis for precision oncology, enabling predictive biomarkers, combination strategies, and novel interventions to address the dynamic challenges of cancer.

This schematic illustrates the central role of lactylation, a lactate‐derived posttranslational modification, in linking metabolic reprogramming to cancer progression and therapy resistance. At its core, lactylation modulates proteins, influenced by metabolic shifts and environmental factors. The key pathways involved in this process include glucose metabolism via the tricarboxylic acid (TCA) cycle, producing lactate that drives protein lactylation and lowers the extracellular pH, generating an acidic tumor microenvironment (TME). Regarding drug response, lactylation affects chemotherapy response by regulating DNA modification as well as tumor proliferation and apoptosis (arrows represent promotion and termination lines represent inhibition). The lactylation of functional proteins and histones may influence the mechanism of targeted drug action, as lactylation modification of the target protein itself could potentially lead to resistance or loss of efficacy of targeted therapies. Lactylation can also weaken the therapeutic efficacy of CAR‐T cell therapy and other immunotherapies, and may also induce an inhibitory TME. Regarding factors affecting lactylation, competing modifications like acetylation (Ac), ubiquitination (Ub), and phosphorylation (P) integrate with lactylation. External factors encompass genetic mutations, signaling pathways, the gut microbiome, drugs, viruses, and pollutants like PM2.5; all of these reprogram metabolism. Overall, lactylation, as a metabolic‐epigenetic nexus, serves as a target for enhancing cancer therapies by disrupting lactate‐driven metabolic reprogramming.