REVIEW article
Front. Oncol.
Sec. Cancer Metabolism
This article is part of the Research TopicMetabolic Reprogramming in Gastrointestinal Cancers: Crosstalk Between Tumor Plasticity and Therapy ResistanceView all articles
Lactate Metabolism and Protein Lactylation in Colorectal Cancer: From Metabolic Reprogramming to Epigenetic Regulation
Provisionally accepted
- 1The Second Clinical Medical College, Lanzhou University, Lanzhou, China
- 2Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- 3Department of Pathology, Lanzhou University Second Hospital, Lanzhou, China
- 4Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
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Colorectal cancer (CRC) exhibits profound metabolic reprogramming, in which excessive lactate accumulation remodels the tumor microenvironment and promotes immune suppression, angiogenesis, and therapeutic resistance. Recent studies reveal that lactate also serves as a substrate for lysine lactylation (Kla), linking metabolic overflow to epigenetic regulation. This review focuses on CRC but also incorporates mechanistic data from other tumor models when CRC-specific evidence is limited, synthesizing lactate metabolism, transport, and lactylation into a unified lactate–lactylation axis. Mechanistic analyses highlight the roles of glycolytic enzymes, monocarboxylate transporters (MCT1/4–CD147), and Kla writers, erasers, and readers in driving malignant progression. Based on these insights, a three-step therapeutic framework is proposed: lowering lactate production, blocking lactate shuttling, and restraining Kla-mediated transcriptional reprogramming. Biomarker-guided evaluation using serum lactate dehydrogenase (LDH), tissue Kla immunohistochemistry, and hyperpolarized [1-^13C]-pyruvate MRI provides translational feasibility. This axis offers a mechanistic basis and actionable targets for metabolism-driven precision therapy, particularly in microsatellite-stable CRC (MSS CRC).
Keywords: biomarkers, colorectal cancer, Immunotherapy, lactate metabolism, lactylation, monocarboxylate transporters, Tumor Microenvironment
Received: 07 Nov 2025; Accepted: 13 Feb 2026.
Copyright: © 2026 Song, Zou, Wu, Ren, Yuan, Pan and Pan. 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) or licensor 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.
* Correspondence: Jiebin Pan
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