Engineering metal-organic framework nanoparticles trigger pyroptosis to boost colon cancer immunotherapy

[Display omitted] •A doxorubicin-loaded metal–organic framework nanoplatform (DOX@Zr-MOF) enabled high drug loading efficiency and excellent pH-responsive degradation.•DOX@Zr-MOF induced pyroptosis-mediated cell death to significantly inhibit colon cancer growth in vitro and in vivo.•DOX@Zr-MOF synergized with programmed cell death-1 (PD-1) antibody could elicit an immune response to enhance antitumor immunotherapy. Pyroptosis, which is a novel form of immunogenic cell death, plays a vital role in antitumor therapy. Zirconium-based metal–organic frameworks (Zr-MOFs) have been applied in various antitumor treatments. However, the intrinsic role of these frameworks in pyroptosis has yet to be determined. Here, a Zr-MOF-based nanosystem (DOX@Zr-MOF) was constructed by loading Zr-MOF nanoparticles with the chemotherapeutic drug doxorubicin (DOX) to synergistically trigger cancer cell pyroptosis. We found that DOX@Zr-MOF rapidly triggered pyroptosis via activation of the canonical caspase-3/gasdermin E (GSDME)-dependent pathway, resulting in significant suppression of CT26 colon tumor growth in vitro and in vivo. Furthermore, DOX@Zr-MOF significantly enhanced the systemic antitumor immune response by reprogramming the immunosuppressive tumor microenvironment. In addition, the combination of DOX@Zr-MOF with programmed cell death-1 (PD-1) immunotherapy strongly improved the antitumor efficacy of CT26 colon tumors. Overall, this work provides a promising strategy for pyroptosis-mediated anticancer treatment, which may efficiently improve checkpoint blockade-related cancer immunotherapy.