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

Abstract 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.