Abstract
ABSTRACT
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.