# Lactylation in colorectal cancer: Unveiling novel mechanisms in metabolism, progression and therapeutic targeting

## TL;DR

This review explores how lactylation, a new type of protein modification, influences colorectal cancer growth, immune evasion, and resistance to treatment.

## Contribution

This is the first comprehensive review of lactylation's role in colorectal cancer, revealing its connection to metabolism, immune evasion, and chemoresistance.

## Key findings

- Lactylation links glycolysis to aggressive cancer behaviors like proliferation and metastasis.
- Lactylation promotes immune evasion by altering the tumor microenvironment.
- Lactylation contributes to resistance against chemotherapy drugs like 5-fluorouracil and oxaliplatin.

## Abstract

Colorectal cancer is a leading cause of cancer mortality characterised by a unique metabolic microenvironment and complex interactions with the gut microbiota. Lactylation, a novel post‐translational modification derived from lactate, has emerged as a key epigenetic regulator connecting metabolic reprogramming to gene expression. While its general roles in cancer are recognised, the tissue‐specific regulatory network of lactylation in colorectal cancer—particularly its interplay with the gut microbiome and specific chemotherapy resistance mechanisms—remains underexplored.

This review systematically dissects the dynamic ‘writer‒eraser‒reader’ network of lactylation, highlighting its distinct oncogenic functions in colorectal cancer. We reveal a critical ‘microbiome‒metabolism‒epigenetics’ axis in which gut flora‐derived metabolites (including D‐lactate) remodel the tumour microenvironment and drive immune evasion. Beyond histone modifications, we emphasise the pivotal role of non‐histone lactylation targets (e.g., eEF1A2, PD‐L1) in orchestrating malignant proliferation and promoting liver metastasis by priming the pre‐metastatic niche. Furthermore, we elucidate novel mechanisms by which lactylation induces resistance to standard chemotherapeutic agents (5‐fluorouracil and oxaliplatin), specifically through the enhancement of DNA repair and the suppression of ferroptosis. We also critically evaluate the pharmacological challenges hindering clinical translation, such as the poor selectivity of current broad‐spectrum inhibitors.

Lactylation serves as a fundamental metabolic‒epigenetic link driving aggressive phenotypes in colorectal cancer. By delineating these tissue‐specific mechanisms and proposing next‐generation site‐specific targeting strategies, this review provides a theoretical foundation for developing precision medicine interventions to overcome therapy resistance in colorectal cancer patients.

This review is the first to summarise the role of lactylation in colorectal cancer (CRC) pathogenesis comprehensively.We discover that lactylation acts as a crucial metabolic sensor linking glycolysis to CRC malignant behaviours.Our study finds that lactylation promotes CRC immune evasion by modulating the tumour microenvironment.We demonstrate that lactylation contributes significantly to chemoresistance in CRC cells.This work provides a new theoretical basis for targeting lactate metabolism and lactylation in CRC therapy.

This review is the first to summarise the role of lactylation in colorectal cancer (CRC) pathogenesis comprehensively.

We discover that lactylation acts as a crucial metabolic sensor linking glycolysis to CRC malignant behaviours.

Our study finds that lactylation promotes CRC immune evasion by modulating the tumour microenvironment.

We demonstrate that lactylation contributes significantly to chemoresistance in CRC cells.

This work provides a new theoretical basis for targeting lactate metabolism and lactylation in CRC therapy.

Lactate accumulation links metabolic reprogramming to epigenetic regulation via protein lactylation. Lactylation drives colorectal cancer proliferation, metastasis, immune escape and chemoresistance. Microbiota‐derived lactate shapes a tumour‐specific lactylation landscape in colorectal cancer. Targeting lactylation pathways offers new opportunities for precision cancer therapy.