An acid-responsive MOF nanomedicine for augmented anti-tumor immunotherapy via a metal ion interference-mediated pyroptotic pathway

Pyroptosis is an inflammatory form of programmed cell death (PCD) that is regulated by the Gasdermin protein family in response to various stimuli, playing a critical role in the development of tumor therapy strategies. However, cancers are generally known to escape from PCD via immunosuppressive pathways or other resistant mechanisms. In this study, an acid-responsive Fe/Mn bimetal-organic framework nanosystem carrying metal ions and immune adjuvant R848 (FeMn@R@H) was designed for combining pyroptosis and augmented immunotherapy. The FeMn@R@H would be triggered to disintegrate and release Fe3+ and Mn2+ ions in response to the acidic tumor microenvironment (TME), thereby initiating Fenton-like reactions for ROS-mediated pyroptosis. On the one hand, the pyroptosis-caused cell rupture would induce the release of proinflammatory cytokines and immunogenic constituents from tumor cells, further resulting in immunogenic cell death (ICD) to promote antitumor immune responses. On the other hand, the co-delivered R848 could reverse suppressive tumor immune microenvironment (TIME) and induce inflammatory responses by activating the TLR7/8 pathway. In conclusion, this tumor-specific therapy system can co-deliver metal ions and R848 to tumor tissues to perform pyroptosis-mediated PCD and augmented anti-tumor immunotherapy. A tumor microenvironment-responsive Fe/Mn bimetal-organic framework nanosystem (FeMn@R@H) was designed to simultaneously deliver the therapeutic metal ions and immune adjuvant R848 for tumor treatment via combing the pyroptosis-induced immunogenic effects and the TLR7/8 pathway-augmented immunotherapy to overcome the immune compensate regulation and the intrinsic immune escape mechanism of tumors. [Display omitted] •The FeMn@R@H was developed to deliver the therapeutic metal ions and R848.•The FeMn@R@H enhanced tumor treatment via pyroptosis and immunotherapy.•The FeMn@R@H generated ROS to activate the NLRP3 signaling pathway for pyroptosis.•The pyroptosis resulted in ICD effect to activate antitumor immune responses.•The loaded R848 in FeMn@R@H augmented immunotherapy by activating TLR7/8 pathway.