Abstract The efficacy of combination immunotherapy has been limited by tumor specificity and immune‐related adverse events (irAEs). Herein, we report the development of polymeric STING pro‐agonists (PSPA), whose sono‐immunotherapeutic efficacy is activated by sono‐irradiation and elevated glutathione (GSH) within the tumor microenvironment (TME). PSPA is composed of sonosensitizers (semiconducting polymer) and STING agonists (MSA‐2) via the GSH‐activatable linkers. Under sono‐irradiation, PSPA serves as a sonosensitizer to generate 1O2 and induce immunogenic cell death (ICD) of malignant tumor cells. Furthermore, MSA‐2 is released specifically in tumor microenvironment with highly expressed GSH, minimizing off‐target side effects. The activation of the STING pathway elevates the interferon‐β level and synergizes with SDT to enhance the anti‐tumor response. Therefore, this work proposes a universal approach for spatiotemporal regulation of cancer sono‐immunotherapy.
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