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<p>Emerging evidence shows DNA damage response (DDR) deficiencies can improve immunotherapy efficacy through increasing immunogenicity and immune response. ATR kinase is the core mediator of the initialing DDR signal. ATR inhibition and immunotherapy have been combined in clinical trials over past few years, but the underlying mechanisms remain unclear. Leveraging RNA-seq analysis, we utilized human non-small cell lung cancer (NSCLC) cell lines (A549, H1299) for in vitro assays and a syngeneic mouse Lewis Lung carcinoma (LLC) subcutaneous tumor model for in vivo studies to investigate the phenotypic and mechanistic impact of the ATR inhibitor VX970 in sensitizing immunotherapy. Subsequently, mechanistic investigations were performed utilizing flow cytometry, immunoblotting, immunofluorescence, ELISA, and other molecular assays. Collectively, using these approaches, we identify the impact of ATR inhibition on tumor microenvironment in NSCLC tumors. ATR inhibition was associated with activation of the TBK1-NFκB pathway, increased concentration of the chemokines of CCL2 and CCL20, and improved the T-cell function, in response to accumulating DNA damage. Increased CCR6 + innate lymphoid cell type 3 (ILC3) accumulation was observed in tumors and draining lymph nodes following ATR inhibition. Furthermore, ATR inhibition was associated with enhanced MHC-I expression on the tumor cell surface, accompanied by impaired autophagy flux. These effects were further enhanced in the syngeneic mouse lung tumor model when ATR inhibition was combined with anti-PD-L1. Collectively, these findings suggest that ATR inhibition may enhance tumor sensitivity to immunotherapy by supporting both initial immune recognition and subsequent T cell-mediated antitumor responses.</p>

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ATR inhibition potentiates immunotherapy efficacy via TBK1-NFκB signaling and autophagy blockade in non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Guo Li,
  • Lingping Kong,
  • Shasha Guan,
  • Lu Xu,
  • Jing Wang,
  • Diansheng Zhong,
  • Linlin Zhang

摘要

Emerging evidence shows DNA damage response (DDR) deficiencies can improve immunotherapy efficacy through increasing immunogenicity and immune response. ATR kinase is the core mediator of the initialing DDR signal. ATR inhibition and immunotherapy have been combined in clinical trials over past few years, but the underlying mechanisms remain unclear. Leveraging RNA-seq analysis, we utilized human non-small cell lung cancer (NSCLC) cell lines (A549, H1299) for in vitro assays and a syngeneic mouse Lewis Lung carcinoma (LLC) subcutaneous tumor model for in vivo studies to investigate the phenotypic and mechanistic impact of the ATR inhibitor VX970 in sensitizing immunotherapy. Subsequently, mechanistic investigations were performed utilizing flow cytometry, immunoblotting, immunofluorescence, ELISA, and other molecular assays. Collectively, using these approaches, we identify the impact of ATR inhibition on tumor microenvironment in NSCLC tumors. ATR inhibition was associated with activation of the TBK1-NFκB pathway, increased concentration of the chemokines of CCL2 and CCL20, and improved the T-cell function, in response to accumulating DNA damage. Increased CCR6 + innate lymphoid cell type 3 (ILC3) accumulation was observed in tumors and draining lymph nodes following ATR inhibition. Furthermore, ATR inhibition was associated with enhanced MHC-I expression on the tumor cell surface, accompanied by impaired autophagy flux. These effects were further enhanced in the syngeneic mouse lung tumor model when ATR inhibition was combined with anti-PD-L1. Collectively, these findings suggest that ATR inhibition may enhance tumor sensitivity to immunotherapy by supporting both initial immune recognition and subsequent T cell-mediated antitumor responses.