Aptamer‐Engineered Liposomal Platform Enables in Situ cDC1 Vaccination to Potentiate Immunotherapy in Prostate Cancer

ABSTRACT Prostate cancer (PCa) is a prototypical “cold tumor” with low immunogenicity and a highly immunosuppressive tumor microenvironment, which severely limits the efficacy of immunotherapy. Notably, the number and functionality of conventional type 1 dendritic cells (cDC1), which are critical antigen‐presenting cells, are markedly reduced in PCa, thereby impairing T cell priming. Here, we developed an aptamer‐modified liposomal platform (Apt‐Flt3L@Lipo) for the targeted co‐delivery of Flt3 ligand (Flt3L) and chlorin e6 (Ce6) to elicit in situ cDC1 vaccination. Upon ultrasound activation, Ce6 induced immunogenic cell death (ICD) in tumor cells, releasing abundant tumor antigens, while the concurrently released Flt3L promoted the differentiation and intratumoral recruitment of cDC1s. Thus, by coupling antigen release with cDC1 activation, we generated an in situ cDC1 vaccine, which enhanced antigen cross‐presentation, primed CD8 ⁺ T cells, and robustly suppressed tumor progression. When combined with immune checkpoint blockade (ICB), the strategy synergistically controlled both primary and distant tumors. In a patient‐derived ex vivo explant and transwell validation models, this approach demonstrated strong translational potential for inducing effective anti‐tumor immunity. Collectively, this platform offered a novel immunotherapy strategy for treating immunologically “cold” prostate cancer with strong potential for clinical translation.