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<p>Interferon-beta (IFN-β) has potent antitumor activity, but its clinical therapeutic potential is undermined by intrinsic negative feedback loops that suppress IFN-β production. However, the feedback mechanisms regulating IFN-β homeostasis in non-small cell lung cancer (NSCLC) remain unclear. We found that tripartite motif containing 3 (TRIM3) promotes the transcription and mRNA expression of <i>IFNB1</i>. Conversely, excessive IFN-β inhibits expression of TRIM3, creating their reciprocal feedback loop. Mass spectrometry revealed that toll-like receptor 3 (TLR3), a key sensor that triggers IFN-β production, is the interacting partner of TRIM3. Following the elucidation of the interactive mode between TRIM3 and TLR3, we found that activation of the TRIM3/TLR3 axis induced IFN-β secretion and overrode the feedback inhibition. Sustained IFN-β secretion subsequently inhibits NSCLC cell proliferation and reprograms the tumor microenvironment by increasing the infiltration levels of CD4<sup>+</sup> T cells, M1 macrophages and NK cells. Our findings revealed a reciprocal negative feedback loop in the regulation of IFN-β signaling, highlighting the role of the TRIM3/TLR3 axis in the suppression of NSCLC progression and offering a promising strategy to suppress tumor growth and enhance immunotherapy efficacy in NSCLC.</p>

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The TRIM3/TLR3 axis overrides IFN-β feedback inhibition to suppress NSCLC progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Jianyu Xu,
  • Qianfang Hu,
  • Ying Zhu,
  • Qian Liu,
  • Feng Wang,
  • Yanxia Yu,
  • Wenjuan Wang,
  • Xinyuan Ding

摘要

Interferon-beta (IFN-β) has potent antitumor activity, but its clinical therapeutic potential is undermined by intrinsic negative feedback loops that suppress IFN-β production. However, the feedback mechanisms regulating IFN-β homeostasis in non-small cell lung cancer (NSCLC) remain unclear. We found that tripartite motif containing 3 (TRIM3) promotes the transcription and mRNA expression of IFNB1. Conversely, excessive IFN-β inhibits expression of TRIM3, creating their reciprocal feedback loop. Mass spectrometry revealed that toll-like receptor 3 (TLR3), a key sensor that triggers IFN-β production, is the interacting partner of TRIM3. Following the elucidation of the interactive mode between TRIM3 and TLR3, we found that activation of the TRIM3/TLR3 axis induced IFN-β secretion and overrode the feedback inhibition. Sustained IFN-β secretion subsequently inhibits NSCLC cell proliferation and reprograms the tumor microenvironment by increasing the infiltration levels of CD4+ T cells, M1 macrophages and NK cells. Our findings revealed a reciprocal negative feedback loop in the regulation of IFN-β signaling, highlighting the role of the TRIM3/TLR3 axis in the suppression of NSCLC progression and offering a promising strategy to suppress tumor growth and enhance immunotherapy efficacy in NSCLC.