Decoding osteosarcoma mechanobiology: PIEZO channels in tumor progression, immune remodeling, and pain.

Osteosarcoma arises in a mechanically active skeletal environment, but how physical cues shape tumor behavior, immunity, and pain remains poorly defined. This review examines PIEZO1 and PIEZO2 as compartment-specific mechanotransducers and distinguishes direct osteosarcoma evidence from disease-relevant preclinical findings and broader evidence from bone, immune, neural, and pain systems. PIEZO1 is best established in osteoblast-lineage cells and osteocytes, where it regulates bone remodeling and mechanical adaptation; its causal role in human osteosarcoma remains unresolved. In osteosarcoma models, PIEZO1-associated responses to stiffness and strain are linked to invasion, adhesion remodeling, YAP/TAZ signaling, and phenotypic plasticity. PIEZO2 is less well supported as a tumor-cell regulator and is more convincingly positioned in sensory neurons that mediate mechanically evoked bone cancer pain. PIEZO1 may also influence myeloid, dendritic-cell, and T-cell behavior, although this immune axis remains unvalidated in osteosarcoma. These compartment-specific roles expose a mechanotherapeutic paradox: pathways required for skeletal adaptation and repair may also be used by malignant or stromal compartments. Resolving this problem will require spatially resolved human studies, orthotopic immunocompetent models, and cell-type-selective perturbation.