A TAK1 cytokine toxicity checkpoint controls anti-cancer immunity

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<sup>+</sup> 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.

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Publication Details

Journal
Cell Reports
Published
2025-12-19
DOI
https://doi.org/10.1016/j.celrep.2025.116665
Primary Topic
NF-κB Signaling Pathways
Type
article
Field-Weighted Citation Impact
0.00
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article

A TAK1 cytokine toxicity checkpoint controls anti-cancer immunity

Lisa A. Mielke, Akash Srivaths, Tirta M. Djajawi, Dáire Gannon et al.
Cell Reports
NF-κB Signaling Pathways
article

A TAK1 cytokine toxicity checkpoint controls anti-cancer immunity

Lisa A. Mielke, Akash Srivaths, Tirta M. Djajawi, Dáire Gannon, Liam Neil, Laura J. Jenkins, Joseph A. Trapani, John M. Mariadason, Hao Dong, Andreas Behren, Séamus J. Martin, Vivien R. Sutton, Kok Fei Chan, Gökhan Günay, Matthias Ernst, Stephin J. Vervoort, Emily J. Lelliott, Bhupinder Pal, Conor J. Kearney, Rebecca Feltham, Maede Salehi, S. Rivera, Olivia Voulgaris, A. Halawani, Anne Huber, Nooshin Khoshdoozmasouleh, Chloe Gerak, Oliver Ozaydin
article en

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<sup>+</sup> 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.

Cell ReportsVol. 45(1)
Walter and Eliza Hall Institute of Medical Research (AU), Trinity College Dublin (IE), Peter MacCallum Cancer Centre (AU), Olivia Newton-John Cancer Wellness & Research Centre (AU)
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NF-κB Signaling Pathways
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