921 Calcium-stabilized nanocomplex for intravesical co-delivery of TLR7/8 agonist and chemotherapy to enhance anti-tumor immune responses in bladder cancer

Background Non-muscle invasive bladder cancer (NMIBC) lacks highly effective first-line treatments. Although Bacillus Calmette-Guérin (BCG) instillation aims to activate antitumor immunity and prevent recurrence, its clinical efficacy remains suboptimal. Tumor-associated macrophages (TAMs), which drive immunosuppression and therapy resistance, are associated with poor prognosis in bladder cancer, making them a promising therapeutic target.Methods We developed a biodegradable, calcium-linked poly(aspartic acid) (PASP) nanocomplex for intravesical co-delivery of doxorubicin (DOX) and the TLR7/8 agonist IMDQ. This nanosystem localizes within the bladder wall and responds to the acidic tumor microenvironment by releasing its payload. DOX induces immunogenic cell death (ICD), enhancing tumor antigen exposure, while IMDQ reprograms TAMs from pro-tumor (M2-like) to anti-tumor (M1-like) phenotypes, activates antigen-presenting cells, and stimulates T-cell responses.Results The nanocomplex significantly suppressed bladder tumor growth and reduced recurrence by synergizing chemotherapy and immunotherapy. DOX-mediated ICD amplified tumor antigen availability, while IMDQ-driven macrophage polarization and dendritic cell activation promoted a robust antitumor immune response. Local intravesical delivery minimized systemic toxicity while maximizing drug retention in the bladder.Conclusions This calcium-stabilized PASP nanocomplex represents a novel intravesical immunotherapy-chemotherapy strategy that reprograms TAMs, enhances antitumor immunity, and overcomes BCG limitations. Its localized action and dual-drug synergy offer a clinically translatable approach for improving NMIBC treatment ( figure 1).Abstract 921 Figure 1Graphical abstract