Cytoskeleton governs exosome-mediated drug resistance under mechanical stress

Drug resistance remains a critical obstacle in solid tumor therapy. While most studies have focused on chemical signaling within the tumor microenvironment, accumulating evidence has revealed that mechanical stress is a pivotal but underappreciated driver of drug resistance. Unlike previous reviews that have separately addressed mechanotransduction, exosome biology, and autophagy, this review proposes a vertically integrated framework - the "mechanical stress-cytoskeleton-exosomes-autophagy" axis - that connects these domains into a causal cascade from mechanical stress sensing to the dissemination of population-level resistance. Our central hypothesis is that cytoskeletal remodeling, driven by shear stress, matrix stiffness, and compressive stress, not only transduces mechanical signals intracellularly but also encodes these physical cues into exosomal cargo. These exosomes, in turn, transmit stress memory to recipient cells and trigger protective autophagy, thereby propagating drug-resistant phenotypes across heterogeneous tumor regions. We synthesize current evidence across biomechanics, vesicle trafficking, and stress biology and critically evaluate the intervention strategies that target each node of this axis. By reframing drug resistance as a mechanically propagated, exosome-mediated process, this review provides a new conceptual foundation and actionable directions for overcoming treatment failure.