Mechano-metabolic coupling in the tumor microenvironment: from mechanotransduction to protein lactylation and metastatic cascades

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.