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<p>Immunotherapy has emerged as a first-line treatment for patients with advanced non-small cell lung cancer (NSCLC), but over half of patients fail to benefit, largely due to tumor heterogeneity and a complex tumor microenvironment. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a recently identified immune checkpoint ligand, is targeted by tripartite motif-containing protein 21 (TRIM21) for proteasomal degradation, thereby enhancing the anti-tumor activity of cytotoxic T lymphocytes (CTLs). We further show that interferon regulatory factor 1 (IRF1) regulates TRIM21 transcription. Artemisinin upregulates the IRF1-TRIM21 axis, promoting FGL1 degradation. In high FGL1 expressed tumors, artemisinin in combination with anti-programmed cell death protein 1 (anti-PD-1) therapy enhances immunotherapeutic efficacy. Clinically, an elevated FGL1/TRIM21 protein ratio is associated with poor prognosis in NSCLC. Collectively, these findings elucidate a post-translational regulatory mechanism of FGL1 in tumor progression and support the development of a rational combination immunotherapy strategy for NSCLC treatment.</p><p></p>

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Targeting IRF1-TRIM21 axis enhances anti-tumor immunity by promoting ubiquitin-mediated degradation of FGL1 in non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Yuchen Zhang,
  • Pingjing Zhou,
  • Yifan Guo,
  • Hongyu Zhang,
  • Guangyin Zhao,
  • Jun Yin,
  • Di Ge,
  • Ronghua Liu,
  • Jie Gu,
  • Chunyi Zhang

摘要

Immunotherapy has emerged as a first-line treatment for patients with advanced non-small cell lung cancer (NSCLC), but over half of patients fail to benefit, largely due to tumor heterogeneity and a complex tumor microenvironment. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a recently identified immune checkpoint ligand, is targeted by tripartite motif-containing protein 21 (TRIM21) for proteasomal degradation, thereby enhancing the anti-tumor activity of cytotoxic T lymphocytes (CTLs). We further show that interferon regulatory factor 1 (IRF1) regulates TRIM21 transcription. Artemisinin upregulates the IRF1-TRIM21 axis, promoting FGL1 degradation. In high FGL1 expressed tumors, artemisinin in combination with anti-programmed cell death protein 1 (anti-PD-1) therapy enhances immunotherapeutic efficacy. Clinically, an elevated FGL1/TRIM21 protein ratio is associated with poor prognosis in NSCLC. Collectively, these findings elucidate a post-translational regulatory mechanism of FGL1 in tumor progression and support the development of a rational combination immunotherapy strategy for NSCLC treatment.