Cancer stem cells (CSCs) contribute to chemotherapy resistance and poor prognosis, posing significant challenges in the treatment of oral squamous cell carcinoma. The extracellular matrix (ECM)-constructed microenvironment remodels the niche of CSCs. Yet mechanisms by which biophysical properties of ECM relate to CSCs remain undefined. Here, our findings link ECM mechanical stimuli to CSCs phenotype transition, and propose that ECM stiffening mechanoactivates tumor cells to dedifferentiate and acquire CD44+ stem cell-like characteristics through noncanonical mechanotransduction. ITGB1 senses and transduces biomechanical signals, while FERMT1 acts as an intracellular mechanotransduction downstream, activating CSCs. Mechanistically, FERMT1 promotes the proteasomal degradation of CK1α by E3 ubiquitin ligase MIB1, thereby triggering Wnt signaling pathway. Combining targeted ECM softening with mechanotransduction inhibition strategy significantly attenuates tumor stemness and chemoresistance in vivo. Therefore, our findings highlight the role of ECM in regulating CSCs via biomechanical-dependent manner, suggesting the ECM/ITGB1/FERMT1/Wnt axis as a promising therapeutic target for CSCs therapy.
© 2025. The Author(s), under exclusive licence to Springer Nature Limited.