A TAK1 cytokine toxicity checkpoint controls anti-cancer immunity
- Author(s)
- Djajawi, TM; Huber, A; Rivera, SM; Srivaths, A; Salehi, M; Gunay, G; Gerak, C; Neil, L; Ozaydin, O; Voulgaris, O; Al Halawani, A; Gannon, D; Khoshdoozmasouleh, N; Jenkins, LJ; Chan, KF; Behren, A; Ernst, M; Mielke, LA; Lelliott, EJ; Dong, H; Feltham, R; Sutton, VR; Trapani, JA; Mariadason, JM; Pal, B; Martin, SJ; Vervoort, SJ; Kearney, CJ;
- Journal Title
- Cell Reports
- Publication Type
- Online publication before print
- 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.
- Keywords
- CP: cancer; CP: immunology; Crispr; Tak1; Tnf; cFLIP; immunotherapy; interferon gamma
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1016/j.celrep.2025.116665
- Open Access at Publisher's Site
https://doi.org/10.1016/j.celrep.2025.116665- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-01-20 05:38:36
Last Modified: 2026-01-20 05:38:55