Bioactivable STING Nanoagonists to Synergize NIR‐II Mild Photothermal Therapy Primed Robust and Long‐Term Anticancer Immunity

Abstract Pharmacological activation of the stimulator of interferon genes (STING) pathway has become a promising strategy for cancer immunotherapy. However, the insufficient tumorous accumulation, rapid clearance, and short duration of drug efficacy in the tumor microenvironment of small structural STING agonists greatly compromise the therapeutic efficacy. Herein, a tumorous extracellular matrix (ECM) is presented anchoring STING agonist‐based photoimmunothernostic nanomedicine (SAPTN) that can be activated by mild‐temperature photothermal therapy (mild PTT) induced neutrophilic inflammation. The SAPTN owns second window near‐infrared (NIR‐II) photonics properties fitting for NIR‐II fluorescence and photoacoustic imaging‐guided cancer therapy. The aggregates SAPTN targeting to the ECM provide slow and continuous release of potent STING agonists diABZIs. The mild PTT and long‐lasting STING agonists released in the ECM synergistically prime systematic, robust, and long‐term anticancer immunity. In a tumor model, this approach leads to complete tumor eradication in about 100% of mice with orthotopic breast tumors, and the mice regained tumor‐free survival of at least 2 months. In addition, the immune‐mediated abscopal effect shows inhibition of the distant solid tumor growth by intratumoral administration of SAPTN with laser irradiation. Overall, this approach represents a generalized photoactivable nanomedicine to prime anticancer immunity for improved cancer theranostics.