A TAK1 cytokine toxicity checkpoint controls anti-cancer immunity
Year: 2025
Type: article
Abstract: Cancer immunotherapies benefit only a subset of patients, highlighting the need to define tumor-intrinsic mechanisms of immune evasion. Using a kinome-wide CRISPR-Cas9 screen, we identify MAP3K7 (transforming growth factor beta-activated kinase 1 [TAK1]) as a checkpoint that protects cancer cells from CD8 + T cell-mediated killing. TAK1 integrates tumor necrosis factor (TNF) and interferon gamma (IFNγ) signals to drive a cytoprotective response that blocks cytokine-induced death and prevents bystander killing by perforin-deficient T cells. Inhibition of TAK1 redirects TNF/IFNγ signaling toward apoptosis via RIPK1 and caspase-8 while simultaneously amplifying IFNγ outputs to further prime cells for cytokine-driven death. Mechanistically, TAK1 loss triggers proteasomal degradation of cFLIP, promoting complex II formation and undermining protective pathways. In immune-competent mice, TAK1 deficiency markedly impairs tumor growth, whereas immune-deficient hosts show little effect. Adoptive T cell therapy preferentially eliminates TAK1-deficient clones. These findings establish TAK1 as a tumor-intrinsic immune checkpoint and support TAK1 inhibition as a strategy to enhance cancer immunotherapy.
Source: Cell Reports
Authors: Tirta M. Djajawi, Anne Huber, Sarahi Mendoza Rivera, Akash Srivaths, Maede Salehi, Gokhan Gunay, Chloe Gerak, Liam Neil, Oliver Ozaydin, Olivia Voulgaris, Aleen Al Halawani, Dáire Gannon, Nooshin Khoshdoozmasouleh, Laura J. Jenkins, Kok Fei Chan, Andreas Behren, Matthias Ernst, Lisa A. Mielke, Emily J. Lelliott, Hao Dong, Rebecca Feltham, Vivien R. Sutton, Joseph A. Trapani, John M. Mariadason, Bhupinder Pal, Seamus J. Martin, Stephin J. Vervoort, Conor J. Kearney
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
OpenAlex ID: W4417504883