Multifunctional nanoagonist enhances photodynamic therapy-driven in situ cancer vaccination by inhibiting tumor thrombosis

Converting autologous tumors into therapeutic cancer vaccines represents an attractive strategy for achieving personalized antitumor immunity. However, the antitumor immune response is significantly compromised by the tumor microenvironment (TME). Herein, we developed a polymersomal nanoagonist (cDVPMA) to potentiate photodynamic therapy (PDT)-driven in situ cancer vaccination (ISCV) by inhibiting intratumoral thrombosis. cDVPMA was constructed by encapsulating the stimulator of interferon genes (STING) agonist 2'3'-cGAMP in the aqueous core of a tertiary ammonium group-containing polymersome, while embedding both the photosensitizer verteporfin-phospholipid (VL) and thrombin inhibitor dabigatran etexilate within the hydrophobic layer. Upon tumor accumulation, cDVPMA swells in response to the acidic TME, promoting controlled drug release. VL-mediated PDT not only kills cancer cells but also triggers immunogenic cancer cell death and enhances tumor antigen exposure, thus achieving ISCV by synergizing with 2'3'-cGAMP-mediated STING activation. Dabigatran etexilate effectively inhibits tumor thrombosis, thereby restoring tumor microcirculation, alleviating hypoxia, and reducing the secretion of immunosuppressive cytokines. In a 4T1 mouse breast cancer model, cDVPMA combined with near-infrared (NIR) laser irradiation elicited robust antitumor immunity, significantly suppressing primary tumor growth and metastasis, while establishing durable immune memory that prevented tumor recurrence. This study provides valuable insights into the development of nanomedicines for immunotherapy targeting tumors in a hypercoagulable state.