Mechanical regulation of m6A-dependent autophagy sustains cancer stemness and chemoresistance in a viscoelastic tumor microenvironment.
The mechanical properties of the tumor microenvironment fundamentally influence cancer progression, while how viscoelastic cues interface with epitranscriptomic regulation to control cell fate remains poorly understood. Here, a pair of hyaluronic acid-based supramolecular hydrogels with tunable network dynamics are engineered to mimic the viscoelastic properties of tumor ECM. Human osteosarcoma (HOS) cells encapsulated in highly dynamic (HD) hydrogels form compact spheroids, display elevated stemness markers, and exhibit enhanced metabolic activity compared to low-dynamic (LD) matrices. Mechanistic analysis reveals that HD hydrogels strengthen E-cadherin adhesion and activate an AMPK-N6-methyladenosine (m6A) methylation signaling cascade, which increases the translation of FOXO3 mRNA and drives autophagy. This mechanics-driven m6A-autophagy axis maintains self-renewal and promotes chemoresistance. In vivo, HD hydrogel-delivered spheroids exhibit enhanced tumor growth and chemoresistance, while autophagy inhibition markedly improves cisplatin efficacy against the grafted tumors. These findings establish viscoelasticity as a key upstream regulator of m6A-dependent autophagy in osteosarcoma and identify mechanical regulation of m6A modification on specific autophagy-related transcripts as a promising target for combination therapy.