Boronate-crosslinked hydrogel enables localized chemoimmunotherapy to remodel the immune microenvironment in triple-negative breast cancer.

The efficacy of immunotherapy in triple-negative breast cancer (TNBC) critically depends on the infiltration of functional immune cells within the tumor microenvironment (TME). However, TNBC is frequently characterized by insufficient T cell infiltration. To address this limitation, we developed a localized chemoimmunotherapy strategy utilizing an injectable boronate ester-crosslinked hydrogel for co-delivery of doxorubicin (DOX) and an αOX40 antibody. Following intratumoral injection and formation of a local drug depot, released DOX induces immunogenic cell death in tumor cells, while sustained αOX40 antibody delivery provides potent co-stimulatory signals that significantly enhance effector T cell expansion and tumor-killing capacity. In an orthotopic TNBC mouse model, a single intratumoral injection of the therapeutic hydrogel remodeled the TME, shifting it toward a more immunostimulatory state and significantly enhancing therapeutic efficacy. Within post-surgical resection models of breast cancer, the hydrogel effectively reshaped the immunosuppressive post-operative microenvironment. This localized treatment elicited a potent systemic anti-tumor immune response, inhibiting tumor recurrence and lung metastasis while significantly prolonging mouse survival. Notably, approximately 50 % of mice in both the 4 T1 and E0771 post-surgery models achieved complete tumor regression. Furthermore, in an ID8 advanced ovarian cancer peritoneal metastasis model, this therapeutic hydrogel significantly suppressed the growth of intraperitoneal metastatic tumors. Collectively, this versatile localized chemoimmunotherapy strategy represents a promising approach to potentiate antitumor immunity and enhance the effectiveness of cancer immunotherapy.