Abstract Immunosuppressive and homeostatic mechanisms prevent immune cells and tissues from eliminating solid tumors, limiting the efficacy of anti-tumor immunity. Precise dissection of these homeostatic mechanisms can lead to better understanding of how tumors persist and grow within tissues. Our prior studies demonstrate that the A20 protein is a potent regulator of immune homeostasis, regulating both pro-inflammatory and cell death signals. Our recent preliminary data reveal that A20 is highly expressed in tumor microenvironments and that one specific biochemical motif of this protein restrains both acute and anamnestic antitumor immunity. This proposal will dissect the cellular and molecular pathways by which A20 regulates anti-tumor immunity.