Nanoagonist-Mediated GSDME-Dependent Pyroptosis Remodels the Inflammatory Microenvironment for Tumor Photoimmunotherapy

摘要

Immunotherapy, especially immune checkpoint blockade (ICB) antibodyimmunotherapy, has revolutionized the treatment ways of cancers and providedremarkable clinical benefits for multiple cancers. However, the efficacy ofimmunotherapy in tumors with an immune-excluded or immune-suppressedphenotype is dismal due to the lack or paucity of immune infiltration in thetumor microenvironment. Herein, an emerging photoimmunotherapy basedon remodeling the inflammatory microenvironment is reported, ascribed tonanoagonist-mediated gasdermin E (GSDME)-dependent pyroptosis andproviding positive feedback to activate anti-PD-1 immunotherapy. An iridiumbasedphotosensitizer (IrP) carrying methyltransferase inhibitor RG108 (R@IrP)lead to rapid cell pyroptosis via the caspase-3/GSDME pathway under the lightactivation. Furthermore, light-elicited pyroptosis synergized with anti-PD-1 toinduce anti-tumor photoimmunotherapy. The pro-inflammatory factors releasedby pyroptotic cells remodel the inflammatory microenvironment and recruitimmune cells to kill tumor cells, resulting in CD8~+ cytotoxic T lymphocytesactivation, PD-1 expression enhancement, and dendritic cell slightly maturation.Collectively, these findings present a synergistic strategy of photoimmunotherapy,that is, turning immunological cold tumors into hot tumors that canrespond to anti-PD-1-based immunotherapy via precise pathway regulation.