Light-free photochemical internalization-inducing polymer conjugate elicits cancer pyroptosis to coordinate host immune responses

Gasdermin-D-mediated pyroptosis, an immunogenic cell death primarily occurring in antigen-presenting cells, plays a pivotal role in coordinating both innate and adaptive immune responses. Therefore, it holds immense potential for cancer immunotherapy. However, its spatiotemporal control within the tumor microenvironment remains challenging. We developed EPIC (Enzymatically switchable Pyroptosis-Inducing polymer Conjugate) within lysosomes upon exposure to cathepsin B, an enzyme overexpressed in many cancers. Upon in vitro exposure to cancer cells, EPIC generates reactive oxygen species via self-immolation-mediated CRET. The resulting oxidative stress induces lysosomal membrane destabilization, which initiate a downstream signaling cascade leading to proteolytic cleavage of gasdermin-D. The cleaved gasdermin-D assembles into pyroptotic pores in the cell membrane, enabling the efflux of damage-associated molecular patterns and pro-inflammatory cytokines. Systemic administration of EPIC in tumor-bearing mice invokes a potent immune response by dendritic cell maturation and reinvigoration of cytotoxic NK cells. Notably, combining EPIC with anti-PD-1 checkpoint blockade enhances the infiltration of tumor-specific cytotoxic T lymphocytes, resulting in sustained tumor regression and complete remission in over 50% of treated mice. These findings underscore the potential of EPIC as a multifunctional, precisely activatable nanotherapeutic for effective cancer immunotherapy.