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The combination of different checkpoint inhibitors has been shown to benefit some patients with non-small cell lung cancer (NSCLC), but identifying those who are most likely to benefit and sparing patients who will not remains a crucial challenge. Skoulidis et al. show that tumors with mutations in KEAP1 and/or STK11 are more likely to respond to dual PD-L1 and CTLA4 blockade (with the inhibitors durvalumab and tremelimumab, respectively) when combined with chemotherapy.

不同检查点抑制剂的组合已被证明对一些非小细胞肺癌（NSCLC）患者有益，但确定那些最有可能受益的患者，并保留那些不会受益的患者仍然是一个关键的挑战。Skoulidis等人表明，当与化疗联合使用时，KEAP1和/或STK11突变的肿瘤更有可能对双重PD-L1和CTLA4阻断（分别使用抑制剂durvalumab和tremelimumab）产生反应。

This subset of patients did not benefit from chemotherapy and durvalumab together, highlighting the importance of CTLA4 inhibition. In mouse models of NSCLC with mutations in Stk11 or Keap1, the authors observed a distinct portfolio of immune-infiltrating cells in tumors, with specific enrichment of suppressive myeloid cells and a dearth of CD8+ cytotoxic T cells.

这部分患者没有从化疗和durvalumab中获益，突出了CTLA4抑制的重要性。在Stk11或Keap1突变的NSCLC小鼠模型中，作者观察到肿瘤中免疫浸润细胞的独特组合，抑制性骨髓细胞的特异性富集和CD8+细胞毒性T细胞的缺乏。

Treatment with anti-PD-1 and anti-CTLA4 antibodies led to potent tumor regression probably mediated by the activation of CD4+ T cell subsets and a shift in the myeloid compartment toward cells that kill by the production of inducible nitric oxide synthase. Lung cancers driven by mutations in KEAP1 or STK11 are notoriously challenging to treat, so the identification of a potential therapy regimen that is tailored to these alterations is an encouraging step forward.Original reference: Nature https://doi.org/10.1038/s41586-024-07943-7 (2024).

。众所周知，由KEAP1或STK11突变驱动的肺癌治疗具有挑战性，因此确定针对这些改变的潜在治疗方案是令人鼓舞的一步。原始参考：Naturehttps://doi.org/10.1038/s41586-024-07943-7（2024年）。

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Author informationAuthors and AffiliationsNature Genetics https://www.nature.com/ngSafia DanoviAuthorsSafia DanoviView author publicationsYou can also search for this author in

作者信息作者和附属机构成熟遗传学https://www.nature.com/ngSafiaDanoviAuthorsSafia DanoviView作者出版物您也可以在

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Safia Danovi.Rights and permissionsReprints and permissionsAbout this articleCite this articleDanovi, S. Optimizing combination immunotherapy in lung cancer.

Safia Danovi。权利和许可打印和许可本文引用本文Danovi，S。优化肺癌联合免疫治疗。

Nat Genet 56, 2296 (2024). https://doi.org/10.1038/s41588-024-02011-2Download citationPublished: 08 November 2024Issue Date: November 2024DOI: https://doi.org/10.1038/s41588-024-02011-2Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Nat Genet 562296（2024）。https://doi.org/10.1038/s41588-024-02011-2Download引文发布日期：2024年11月8日发布日期：2024年11月OI：https://doi.org/10.1038/s41588-024-02011-2Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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