Mechano-metabolic coupling in the tumor microenvironment: from mechanotransduction to protein lactylation and metastatic cascades
4 affiliations
- 1Hunan University of Chinese Medicine
- 2The First Affiliated Hospital of Hunan University of Chinese Medicine
- 3Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine
- 4Hunan Provincial Key Lab for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Hunan University of Chinese Medicine
Abstract
Aberrant mechanical signals within the tumor microenvironment (TME)—including increased extracellular matrix stiffness, elevated solid stress, heightened interstitial fluid pressure, and fluid shear stress—have been established as key drivers of malignant tumor progression and metastasis. These physical cues are sensed by mechanoreceptors on the cell membrane (Piezo1, TRP channels, and integrin-FAK complexes), transmitted intracellularly through Rho GTPases and cytoskeletal dynamics, and ultimately reprogram transcriptional programs via nuclear translocation of transcriptional co-activators such as YAP/TAZ. Mechanical signals also drive metabolic reprogramming in tumor cells, particularly enhancing aerobic glycolysis (the Warburg effect), which results in massive lactate accumulation. Landmark discoveries in recent years have revealed that lactate serves as a substrate to drive histone and non-histone lactylation, directly coupling metabolic status with epigenetic regulation. Histone lactylation (e.g., H3K18la, H3K9la) activates pro-metastatic transcriptional programs by remodeling chromatin accessibility, promoting epithelial–mesenchymal transition (EMT), immune evasion, and therapeutic resistance; non-histone lactylation directly modifies cytoskeletal proteins (CFL1, vimentin, TPX2) and transcriptional regulators (Snail, YY1, PRMT1), enhancing the metastatic execution capacity of tumor cells at multiple levels, including cellular mechanical properties, migratory ability, and signal transduction. Importantly, mechanical signals, metabolic reprogramming, and lactylation constitute a mechano-metabolism-lactylation positive feedback loop, forming a self-reinforcing vicious cycle that continuously fuels tumor metastasis. This review systematically outlines the types and mechanotransduction mechanisms of TME mechanical signals, mechanically driven metabolic and transcriptional reprogramming, the multifaceted functions of lactylation in tumor metastasis, and the ultimate execution of the metastatic cascade driven by this positive feedback loop, and discusses potential therapeutic strategies targeting mechanosensitive pathways, metabolic vulnerabilities, and lactylation-modifying enzymes.
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BibTeX
@article{zhang2026mechanometabolic,
title = {{Mechano-metabolic coupling in the tumor microenvironment: from mechanotransduction to protein lactylation and metastatic cascades}},
author = {Wenqing Zhang and Huimei Chen and Jingying Fan and Yingchun He and Jie Liu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1991810},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1991810/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mechano-metabolic coupling in the tumor microenvironment: from mechanotransduction to protein lactylation and metastatic cascades
AU - Wenqing Zhang
AU - Huimei Chen
AU - Jingying Fan
AU - Yingchun He
AU - Jie Liu
PY - 2026
DA - 2026/10/27
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1991810
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1991810/full
AB - Aberrant mechanical signals within the tumor microenvironment (TME)—including increased extracellular matrix stiffness, elevated solid stress, heightened interstitial fluid pressure, and fluid shear stress—have been established as key drivers of malignant tumor progression and metastasis. These physical cues are sensed by mechanoreceptors on the cell membrane (Piezo1, TRP channels, and integrin-FAK complexes), transmitted intracellularly through Rho GTPases and cytoskeletal dynamics, and ultimately reprogram transcriptional programs via nuclear translocation of transcriptional co-activators such as YAP/TAZ. Mechanical signals also drive metabolic reprogramming in tumor cells, particularly enhancing aerobic glycolysis (the Warburg effect), which results in massive lactate accumulation. Landmark discoveries in recent years have revealed that lactate serves as a substrate to drive histone and non-histone lactylation, directly coupling metabolic status with epigenetic regulation. Histone lactylation (e.g., H3K18la, H3K9la) activates pro-metastatic transcriptional programs by remodeling chromatin accessibility, promoting epithelial–mesenchymal transition (EMT), immune evasion, and therapeutic resistance; non-histone lactylation directly modifies cytoskeletal proteins (CFL1, vimentin, TPX2) and transcriptional regulators (Snail, YY1, PRMT1), enhancing the metastatic execution capacity of tumor cells at multiple levels, including cellular mechanical properties, migratory ability, and signal transduction. Importantly, mechanical signals, metabolic reprogramming, and lactylation constitute a mechano-metabolism-lactylation positive feedback loop, forming a self-reinforcing vicious cycle that continuously fuels tumor metastasis. This review systematically outlines the types and mechanotransduction mechanisms of TME mechanical signals, mechanically driven metabolic and transcriptional reprogramming, the multifaceted functions of lactylation in tumor metastasis, and the ultimate execution of the metastatic cascade driven by this positive feedback loop, and discusses potential therapeutic strategies targeting mechanosensitive pathways, metabolic vulnerabilities, and lactylation-modifying enzymes.
SN - 1664-3224
ER -