Tumor-Adhesive Chitosan-Derived Multi-Immune Agonist Unleashes Strong and Durable Anti-Cancer Immunity.

The immunomodulation of the tumor microenvironment is critical for effective cancer immunotherapy, particularly for tumors that exhibit limited responses to conventional treatments. However, current immune agonists developed for tumor immunomodulation face several challenges, such as poor intratumoral retention, inadequate biocompatibility, and restricted cellular targets, which ultimately hamper their therapeutic efficacy and clinical application. In this study, a tumor-adhesive chitosan-tethered immune agonist construct (TACTIC) is introduced, which demonstrates good biocompatibility and robust immunostimulatory effects, enhancing the immunogenicity of tumor cells while simultaneously stimulating pro-inflammatory responses in various immune cell populations. Mechanistic investigations reveal that TACTIC targets multiple signaling pathways, conferring it to effectively remodel the irradiated tumor microenvironment, improve tumor control on murine cancer models post-radiotherapy, and elicit systemic immune responses with memory effects. The findings highlight the potential of TACTIC as a powerful macromolecular immune adjuvant, paving the way for its broader application in innovative cancer immunotherapies.