Deconstructing synthetic inflammasomes in tumors drives diverse antitumor responses

Inflammasomes are cardinal defense machines that utilize cytokine and immunogenic cell death components to engage the immune system against pathogens. On the other hand, inflammasomes have ambiguous and context-dependent roles in cancers that are known to downregulate effectors of immunogenic cell death. In this study, we deconstructed inflammasomes by introducing one or both inflammasome signaling arms in diverse types of tumors regardless of the expression of endogenous inflammasome components. To induce immunogenic cell death, we designed tightly regulated GSDMD variants comprising different pore-forming capabilities and diverse modes of activation. We show that electroporation of plasmids encoding the pyroptotic component into B16 melanoma tumors leads to tumor regression and complete remission in a quarter of treated animals. The inflammatory cytokines IL-1β and IL-18, along with the T-cell activator IL-12, did not provide protection when produced solely within tumors. However, they significantly boosted anti-tumor immunity when combined with pyroptosis. Careful selection of immunostimulatory molecules is imperative as a combination of IL-1β and IL-18 or the introduction of IFNγ antagonizes the protective action of pyroptosis by upregulation of several immune checkpoints. Additionally, we show that deconstruction of inflammasomes locally, without inducing systemic inflammation, provides protection against distant tumors and proves effective across various tumor types. Deconstructed inflammasomes are thus a powerful, tunable and tumor-agnostic strategy to enhance antitumor responses to even the most resilient types of tumors.