Mechanical stress, metabolic reprogramming and stromal remodeling: an emerging paradigm in the bladder cancer mechano-micro-environment.

Recently managing bladder cancer (BLCA) has been hampered by two stubborn challenges, one is high recurrence rate in non-muscle-invasive tumors (NMIBC), the other is muscle-invasive disease (MIBC) showed limited responsiveness to immune checkpoint inhibitors (ICIs). Tumor micro-environment (TME) is characterized exclusively, while the physical and mechanical forces that actively remodel tumors have been largely overlooked. The bladder, a mechanically dynamic organ that undergoes continuous cycles of filling and voiding, provides an exceptionally instructive model for dissecting tumor biology driven by mechanical stress. In this review, we systematically delineates how mechanical stresses in BLCA, including extracellular matrix (ECM) stiffening, solid stress, fluid shear stress, and cyclic stretch-drive metabolic reprogramming, resulting in enhanced glycolysis, glutamine metabolic remodeling, and lactate accumulation. These metabolic alterations subsequently promote fibroblast activation, collagen deposition, and lysyl oxidase (LOX)-mediated matrix crosslinking via epigenetic mechanisms such as histone lactylation. Building upon these mechanisms, we propose a therapeutic rationale that jointly targets mechanotransduction, aberrant metabolism, and the immunosuppressive micro-environment, and we further discuss the distinctive translational advantages of intravesical instillation for locoregional combinatorial delivery. This review aims to provide a novel conceptual framework for overcoming intravesical chemoresistance and ICI resistance in BLCA.