Nanomedicine targeting ECM stiffness: restoring mechanical homeostasis for cancer immunotherapy

The pathological stiffening of the extracellular matrix (ECM) in solid tumors drives immunosuppression and therapeutic resistance. However, non-specific ECM degradation has limited clinical benefit and risks promoting metastasis. To address this dilemma, this review proposes a paradigm shift from indiscriminate physical degradation toward spatiotemporally controlled reconstruction of mechanical homeostasis using smart nanomedicine, an approach that lies at the intersection of materials science, cancer biology, and immunotherapy. We first concisely outline how aberrant ECM stiffness drives a vicious cycle of physical immune exclusion, mechanotransduction-mediated immune reprogramming, and reciprocal fibrotic activation. We then critically analyze how advanced nanomedicine platforms can. achieve precise ECM modulation without off-target toxicity. Central to this approach is the "mechano-therapeutic window", an optimal stiffness range that maximizes immune infiltration and therapy sensitization without provoking metastatic risk. Furthermore, we highlight the "priming" strategy, wherein nanomedicine-mediated ECM softening serves as an upstream step to synergistically enhance subsequent immunotherapy, chemotherapy, and radiotherapy, as well as other emerging therapies. Finally, we outline future directions, including the development of adaptive delivery systems that sense and adapt to stiffness dynamics in real-time. By shifting focus from indiscriminate degradation to intelligent mechanical homeostasis, this framework aims to improve cancer immunotherapy outcomes in desmoplastic solid tumors.