Dual-Targeting of ER Stress and the CD47-SIRPα Axis via an In Situ Hydrogel Prevents Postoperative Glioblastoma Recurrence.

The inevitable recurrence of glioblastoma multiforme post-resection is primarily driven by infiltrative residual cells and a profoundly immunosuppressive tumor microenvironment (TME) that evades innate immune surveillance. In the present study, an injectable, photo-crosslinkable carboxymethyl chitosan (CMCS)-based hydrogel (si-HAX1&Quercetin@Gel) was engineered to achieve localized, synergistic chemo-immunotherapy within the surgical cavity. The findings demonstrate that the localized release of si-HAX1 triggers robust endoplasmic reticulum stress-mediated immunogenic cell death, leading to significant CRT surface translocation. Concurrently, Quercetin acts as a small-molecule antagonist of the CD47-signal regulatory protein α axis, dismantling the "don't eat me" shield that protects glioma cells from macrophage-mediated phagocytosis. In an in vivo postoperative glioblastoma model, the si-HAX1&Quercetin@Gel effectively suppressed tumor regrowth, increased the M1/M2 macrophage ratio and recruited CD8+ T cells, thereby extending median survival time. Moreover, this localized intervention sensitized residual tumors to intratumorally administered anti-programmed cell death protein 1 therapy by upregulating IFN-γ and remodeling the TME. By integrating biomaterial engineering with deep molecular targeting of HAX1 and CD47, we provide a robust strategy to transform the post-surgical cavity into an active immunological zone, offering a potent solution to combat malignant glioma recurrence.