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

  • Commun Biol. 2026 Apr 22;9(1):856. doi: 10.1038/s42003-026-10070-w.
Yuchen Zhang  #  1 ,  Pingjing Zhou  #  1 ,  Yifan Guo  #  1  2 ,  Hongyu Zhang  1 ,  Guangyin Zhao  1  2 ,  Jun Yin  1 ,  Di Ge  1 ,  Ronghua Liu  3 ,  Jie Gu  4 ,  Chunyi Zhang  5
Affiliations
  • 1. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2. Department of Thoracic Surgery, Shanghai Geriatric Medical Center, Shanghai, China.
  • 3. Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
  • 4. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 5. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42020516 DOI: 10.1038/s42003-026-10070-w
Abstract

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.

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