Manganese-phenolic nanoadjuvant combines sonodynamic therapy with cGAS-STING activation for enhanced cancer immunotherapy

Dendritic cells (DCs) play a key role in the presentation of tumor antigens to initiate innate and adaptive immune responses. While the tumor microenvironment (TME) contains a network of immunosuppressive factors that inhibit the differentiation and maturation of DCs. Immunoadjuvants have been focusing on modulating DCs function to improve cancer immunotherapy. Herein, a phenolic nanoadjuvant was developed by self-assembly of the sonosensitizer polymer (PEG-b-IR), GSH inhibitor (sabutoclax), Mn2+ and TME acidic sensitive phenolic polymer (PEG-b-Pho) via metal–phenolic coordination. The combinational action of SDT-mediated ICD effect and Mn2+ promoted the activation of the cGAS-STING pathway significantly enhanced DCs maturation. Furthermore, this phenolic nanoadjuvant greatly sensitizes tumors to PD-L1 checkpoint blockade immunotherapy, resulting in efficiently inhibiting the growth of distant tumors and restraining lung metastasis. Therefore, our work provides the potential to remedy the therapeutic limitation of insufficient antitumor immunity for enhanced cancer immunotherapy.