The mechano-immunological barrier in fibrosis-associated lung cancer: targeting matrix stiffness and the Piezo1 axis for microenvironment normalization.

While mechanotransduction influences various lung cancer subtypes, this review focuses specifically on fibrosis-associated non-small cell lung cancer (NSCLC), where the progression from pulmonary fibrosis to malignancy is mediated by aberrant mechanotransduction. Progressive extracellular matrix (ECM) stiffening (8-25 kPa), mediated by lysyl oxidase (LOX)-dependent collagen crosslinking, establishes a "mechano-immunological barrier." This barrier promotes malignant transformation and limits the efficacy of immunotherapy. Piezo1, a mechanically-activated cation channel, regulates this physical remodeling of the tumor microenvironment (TME). In the stiffened fibrotic stroma, mechanical tension activates Piezo1, causing intracellular Ca2+ influx. This influx bypasses canonical Hippo signaling to activate the RCC2-YAP axis and induces "epigenetic mechanical memory" via Rho/ROCK-mediated histone acetylation. Furthermore, Piezo1 modulates local immune responses. Mechanical stress activates Piezo1 in infiltrating T-cell, leading to epigenetic exhaustion and cytoskeletal impairment. Simultaneously, this mechanotransduction polarizes macrophages toward an immunosuppressive M2-like phenotype and mechanically induces PD-L1 expression on tumor cells. This review summarizes the Piezo1-mediated mechanotransduction networks involved in the fibrosis-to-cancer transition. We also discuss emerging "mechano-immunotherapeutics," including targeted Piezo1 modulators, precision nanodelivery systems, and ECM-normalizing agents (e.g., LOX inhibitors and losartan). These strategies demonstrate synergistic effects when combined with immune checkpoint inhibitors. By softening the desmoplastic niche-a tumor-associated microenvironment characterized by excessive fibrous connective tissue and a dense ECM-and modulating mechanosensors, these interventions can convert immunosuppressive "cold" tumors into immunotherapy-responsive "hot" microenvironments.