Targeting tumor intrinsic TAK1 engages TNF-α-driven cell death through distinct mechanisms and enhances cancer immunotherapy.

Despite the success of immune checkpoint inhibitors in cancer, many patients do not respond or relapse following treatment. Therefore, new approaches to augment existing immunotherapies are needed. CRISPR screens have revealed the importance of TNF-α signal transduction mediators, such as TAK1, in facilitating tumor susceptibility to cytotoxic T cells. Here, we demonstrate that inhibition of TAK1 in tumor cells lowers the threshold for TNF-α-induced cytotoxicity. Upon TNF-α signaling, pharmacologic inhibition of TAK1 sensitized tumor cells to RIPK1-dependent apoptosis. However, RIPK1-independent apoptosis occurred upon genetic deletion of Tak1, suggesting a novel scaffolding function of TAK1 is required to induce RIPK1 kinase activity during cell death. Deleting Tak1 impaired in vivo tumor growth, enhanced α-PD-1 immunotherapy, and lead to durable anti-tumor memory, dependent on CD8 T cells and intact TNF-α signaling. Our results collectively demonstrate that compromising TAK1 function within tumor cells leverages the cytotoxic capacity of TNF to enhance anti-tumor immunity and generate deeper and more durable anti-tumor immune responses in preclinical models of cancer.