Enzymatically Switchable Pyroptosis‐Inducing Polymer Conjugate to Coordinate Host Immune Responses in Cancer Immunotherapy

Gasdermin-D-mediated pyroptosis, an immunogenic cell death predominantly occurring in antigen-presenting cells, is pivotal in orchestrating innate and adaptive immunity. Therefore, this dynamic process holds significant potential as an effective cancer immunotherapy strategy. However, its adequate spatiotemporal control in cancer remains challenging. An Enzymatically switchable Pyroptosis-Inducing polymer Conjugate (EPIC) is reported that selectively triggers chemiluminescence resonance energy transfer (CRET) in the lysosome in the presence of Cathepsin B, abundant in cancer cells. When exposed to cancer cells in vitro, EPIC generates reactive oxygen species via self-immolation-mediated CRET, triggering lysosomal membrane disintegration, followed by activation of the signaling cascade that cleaves gasdermin-D. Cleaved gasdermin-D forms pyroptotic pores in the cancer cell membrane, promoting the efflux of damage-associated molecular patterns and inflammatory cytokines. When systemically administered into the tumor-bearing mice, EPIC provokes a robust immune response by promoting dendritic cell maturation and reinvigorating cytotoxic NK cells. Combination of EPIC with anti-PD-1 antibody enhanced infiltration of tumor-specific cytotoxic T cells and promoted memory T cells, resulting in a durable remission of established tumors with complete tumor regression in more than half of the treated mice. Overall, EPIC has potential as a nanoplatform with multifaceted advantages for precise and effective cancer immunotherapy.