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

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.