Reactive oxygen species-responsive pyroptosis nanoinitiators promote immune cell infiltration and activate anti-tumor immune response

Immunotherapy, represented by immune checkpoint inhibitors, has become the standard treatment for a variety of malignant tumors. However, inadequate infiltration of immune cells in tumor tissues and immunosuppressive tumor microenvironment severely limit the efficacy of immunotherapy. In this study, a reactive oxygen species (ROS)-responsive pyroptosis nanoinitiator is developed to precisely trigger pyroptosis of tumor cells, thereby increasing intratumoral immune cell infiltration and activating anti-tumor immune responses. Doxorubicin (DOX) and decitabine (DAC) are encapsulated in the ROS-responsive nanomicelles to prepare the pyroptosis nanoinitiator (M/(DAC+DOX)). After intravenous administration, M/(DAC+DOX) specifically aggregates in tumor tissues and subsequently releases the loaded drugs in response to high concentrations of ROS in tumor cells. DOX and DAC synergistically trigger tumor cell pyroptosis by activating caspase-3 and upregulating Gasdermin E expression, respectively. M/(DAC+DOX) significantly inhibits tumor growth and prolongs the survival time of tumor-bearing mice. Additionally, M/(DAC+DOX) promotes the maturation of dendritic cells, increases the infiltration of cytotoxic T lymphocytes within the tumor, and reduces the proportion of myeloid-derived suppressor cells. Collectively, this study provides a promising strategy for improving the efficacy of immunotherapy and provides a basis for the application of pyroptosis in anti-tumor immunotherapy.