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

Immunotherapy, especially immune checkpoint blockade (ICB) antibody immunotherapy, has revolutionized the treatment ways of cancers and provided remarkable clinical benefits for multiple cancers. However, the efficacy of immunotherapy in tumors with an immune-excluded or immune-suppressed phenotype is dismal due to the lack or paucity of immune infiltration in the tumor microenvironment. Herein, an emerging photoimmunotherapy based on remodeling the inflammatory microenvironment is reported, ascribed to nanoagonist-mediated gasdermin E (GSDME)-dependent pyroptosis and providing positive feedback to activate anti-PD-1 immunotherapy. An iridium-based photosensitizer (IrP) carrying methyltransferase inhibitor RG108 (R@IrP) lead to rapid cell pyroptosis via the caspase-3/GSDME pathway under the light activation. Furthermore, light-elicited pyroptosis synergized with anti-PD-1 to induce anti-tumor photoimmunotherapy. The pro-inflammatory factors released by pyroptotic cells remodel the inflammatory microenvironment and recruit immune cells to kill tumor cells, resulting in CD8(+) cytotoxic T lymphocytes activation, 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 can respond to anti-PD-1-based immunotherapy via precise pathway regulation.