IL1? Promotes Immune Suppression in the Tumor Microenvironment Independent of the Inflammasome and Gasdermin D

Abstract IL1? is a central mediator of inflammation. Secretion typically requires proteolytic maturation by the inflammasome and formation membrane pores gasdermin D (GSDMD). Emerging evidence suggests an important role for in promoting cancer progression patients, but underlying mechanisms are ill-defined. Here, we have shown key driving tumor two distinct mouse models. Notably, activation inflammasome, caspase-8, as well pore-forming proteins GSDMD mixed lineage kinase domain–like protein host were dispensable release intratumoral bioactive IL1?. Inflammasome-independent promoted systemic neutrophil expansion fostered accumulation T-cell–suppressive neutrophils tumor. Moreover, was essential infiltration triggered antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion allowed CD8+ effector T cells that subsequently activated tumor-associated macrophages. Depletion either or macrophages abolished growth inhibition IL1?-deficient mice, demonstrating crucial T-cell–macrophage cross-talk antitumor immune response. Overall, these results support tumor-promoting through establishing immunosuppressive microenvironment show not this cytokine tumors.