Deregulated cell death and inflammation can drive chronic remodelling and tissue repair, which can contribute to cancer and treatment failure. The principle idea addressed by this application is that cell survival and adaptation mechanisms of tumours are supported, at least in part, by cancer-related inflammation, and that this can be successfully targeted by switching the TNF response from pro-inflammation to activation of cell death, causing tumours to permanently regress. Despite clear evidence that TNF can signal cell survival and death, the mechanisms that can switch between the distinct biological outcomes remain elusive. This is important as its resolution, and putative therapeutic intervention, would allow the diversion of cancer-related inflammation into activation of cell death. Our starting point for this proposal is substantial new data on the regulation of TNF-signalling and cell death. We identified that the Ub-receptor function of cIAP1 critically controls TNF signalling, selectively regulating the pro-death effects of TNF, without inhibiting the NFkB pathway. Our preliminary data indicate that a point mutation in the Ub-binding domain of cIAP1, which abrogates its ability to bind to M1- and K63-linked Ub chains, switches the TNF response to cell death, and completely blocks tumorigenesis. Mechanistically, we find that the Ub-binding domain of cIAP1 regulates intracellular trafficking of TNF-R1, and the consequences of RIPK1 ubiquitylation. Our data are consistent with a scenario whereby Ub-binding of cIAP1 participates with ESCRT-0 in capturing and sorting ubiquitylated TNF-R1 and RIPK1 for recycling. Here, we propose to use mouse models, imaging, and biochemical approaches to decipher how the Ub-receptor function of cIAP1 regulates TNF-induced cell death, and whether switching the TNF response from pro-inflammation to cell death is beneficial or harmful in cancer.