Engineered multivalent VCAM1-Fc decoys remodel ECM mechanosensing to suppress H3K18la-driven epigenetic programs and stemness in recurrent glioblastoma

Recurrent glioblastoma (rGBM) exhibits aggressive progression and therapeutic resistance. However, how mechanical cues within the tumor microenvironment contribute to stemness and chemoresistance through mechanotransductive and epigenetic regulation remains incompletely understood. GBM tissues and derived cell models were systematically characterized to examine how defined matrix mechanical conditions are associated with stemness and chemoresistance. Multivalent VCAM1-Fc decoys were engineered to modulate ITGA4-associated mechanosensing, and mechanistic pathways connecting metabolism to mechanotransduction were interrogated using targeted perturbations. rGBM tissues exhibited elevated stiffness and extracellular matrix (ECM) remodeling, which were associated with enhanced stemness and temozolomide resistance alongside increased H3K18 histone lactylation. Stiffness-associated temozolomide (TMZ) resistance manifested as a pre-activated resistance state prior to TMZ exposure and a shielding effect under high-stiffness conditions that further attenuated TMZ efficacy. ITGA4 was identified as a mechanosensing-associated node, and engineered multivalent VCAM1-Fc decoys mediated valency-dependent, reversible competitive inhibition at cell-surface ITGA4, attenuating mechanosensing-associated stemness and chemoresistance without inducing non-specific cytotoxicity. ECM stiffening is linked to stemness maintenance and temozolomide resistance in recurrent GBM through H3K18la-associated epigenetic regulation, while ITGA4/YAP-related mechanosensing provides a membrane-proximal axis that can be attenuated by multivalent VCAM1-Fc. Multivalent VCAM1-Fc may therefore reduce stiffness-associated malignant phenotypes by limiting ITGA4-dependent mechanotransduction.