The glycolysis-H4K12la-PKM2 positive feedback loop drives M2 polarization of macrophages in colorectal cancer.

Authors

Zhuo Zhang, Qiaoling Peng, Shaohu Wang, Quan Xun, Xingming Chen, Mingliang Zhou, Jianguan Luo, Lishun Yang, Chunming Tang, Yiqing Luo, Junlin Liu

Published in

Clinical epigenetics. Jul 13, 2026. Epub Jul 13, 2026.

Abstract

Despite the dominance of M2-polarized tumor-associated macrophages in colorectal cancer (CRC), the metabolic-epigenetic mechanisms by which CRC cells sustain this immunosuppressive phenotype remain elusive. We hypothesize that a glycolysis-driven positive feedback loop, involving PKM2-mediated lactate production and subsequent H4K12 lactylation (H4K12la) at the PKM2 promoter, enables CRC cells to metabolically reprogram macrophages toward M2 polarization. This study aims to characterize this regulatory circuit and determine its potential as a therapeutic target to enhance immunotherapy efficacy.
We used qRT-PCR, Western blot, and metabolic flux analysis (ECAR, lactate production, 2-NBDG uptake) to assess the glycolysis-H4K12la-PKM2 axis in CRC cells following genetic manipulation (PKM2 overexpression/knockdown) and pharmacological inhibition (2-DG). Chromatin immunoprecipitation (ChIP-qPCR) quantified H4K12la enrichment at the PKM2 promoter. The functional impact on macrophage polarization was evaluated using THP-1-derived and primary human macrophage co-culture systems (flow cytometry for CD163), complemented by an in vivo xenograft model.
PKM2 was highly expressed in CRC cells and sustained aerobic glycolysis, leading to elevated intracellular lactate and H4K12la levels. Mechanistically, H4K12la accumulated at the PKM2 promoter, forming a positive feedback loop that amplified glycolytic flux. Disruption of this loop-via PKM2 knockdown or glycolytic inhibition-suppressed M2 macrophage polarization in vitro. In vivo, combined PKM2 knockdown and 2-DG treatment synergistically inhibited tumor growth, reduced M2 macrophage infiltration, and diminished H4K12la levels.
Our findings identify a glycolysis-H4K12la-PKM2 positive feedback loop in CRC cells that drives M2 macrophage polarization. Interrupting this circuit offers a promising strategy to reconfigure the tumor immune landscape and improve immunotherapeutic outcomes.

PMID:
42443977
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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