CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：A TAK1 cytokine toxicity checkpoint controls anti-cancer immunity.
A TAK1 cytokine toxicity checkpoint controls anti-cancer immunity.
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癌症免疫疗法仅对一部分患者有效，这凸显了明确肿瘤内在免疫逃逸机制的必要性。通过全激酶组CRISPR-Cas9筛选，我们鉴定出MAP3K7（转化生长因子β激活激酶1 [TAK1]）作为一种检查点，保护癌细胞免受CD8+ T细胞介导的杀伤。TAK1整合肿瘤坏死因子（TNF）和干扰素γ（IFNγ）信号，驱动一种细胞保护性反应，阻断细胞因子诱导的死亡，并防止穿孔素缺陷T细胞引起的旁观者杀伤。抑制TAK1通过RIPK1和caspase-8将TNF/IFNγ信号重定向至凋亡，同时放大IFNγ输出，进一步使细胞对细胞因子驱动的死亡敏感。在机制上，TAK1缺失触发cFLIP的蛋白酶体降解，促进复合物II形成并破坏保护性通路。在免疫健全小鼠中，TAK1缺陷显著损害肿瘤生长，而免疫缺陷宿主则显示很小的影响。过继性T细胞疗法优先消除TAK1缺陷克隆。这些发现确立了TAK1作为肿瘤内在免疫检查点，并支持抑制TAK1作为增强癌症免疫治疗的策略。
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.
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