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

Jianyu Xu1, Qianfang Hu1, Ying Zhu1

  • 1Department of Pharmacy, Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China.

Cell Death & Disease
|January 16, 2026
PubMed

Insights

Tripartite motif containing 3 (TRIM3) and toll-like receptor 3 (TLR3) activate interferon-beta (IFN-β) production, overcoming feedback inhibition in non-small cell lung cancer (NSCLC). This TRIM3/TLR3 axis suppresses NSCLC progression and enhances immunotherapy.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Interferon-beta (IFN-β) exhibits significant antitumor properties, but its therapeutic application in non-small cell lung cancer (NSCLC) is limited by negative feedback mechanisms that restrict IFN-β production.
  • The precise feedback loops governing IFN-β homeostasis within the NSCLC tumor microenvironment are not fully understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of IFN-β homeostasis in NSCLC.
  • To identify key molecular players involved in IFN-β feedback loops.
  • To explore the therapeutic potential of targeting these mechanisms for NSCLC treatment.

Main Methods:

  • Investigated the role of tripartite motif containing 3 (TRIM3) in IFNB1 gene transcription and expression.
  • Utilized mass spectrometry to identify interacting partners of TRIM3, including toll-like receptor 3 (TLR3).
  • Analyzed the functional consequences of TRIM3/TLR3 axis activation on IFN-β secretion and NSCLC progression.

Main Results:

  • TRIM3 was found to promote IFN-β transcription and expression, while excessive IFN-β reciprocally inhibited TRIM3 expression, establishing a negative feedback loop.
  • TRIM3 interacts with TLR3, a key sensor for IFN-β induction.
  • Activation of the TRIM3/TLR3 axis successfully induced IFN-β secretion, bypassed feedback inhibition, suppressed NSCLC cell proliferation, and enhanced anti-tumor immune cell infiltration (CD4+ T cells, M1 macrophages, NK cells).

Conclusions:

  • A reciprocal negative feedback loop regulating IFN-β signaling in NSCLC was identified, involving TRIM3 and IFN-β.
  • The TRIM3/TLR3 axis plays a critical role in suppressing NSCLC progression by sustaining IFN-β secretion.
  • Targeting the TRIM3/TLR3 axis represents a promising therapeutic strategy to inhibit NSCLC tumor growth and improve immunotherapy outcomes.

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