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  • Title: Targeting the TRIM14/USP14 Axis Enhances Immunotherapy Efficacy by Inducing Autophagic Degradation of PD-L1.
    Author: Liu D, Li M, Zhao Z, Zhou L, Zhi F, Guo Z, Cui J.
    Journal: Cancer Res; 2024 Sep 04; 84(17):2806-2819. PubMed ID: 38924473.
    Abstract:
    Immunotherapy has greatly improved cancer treatment in recent years by harnessing the immune system to target cancer cells. The first immunotherapeutic agent approved by the FDA was IFNα. Treatment with IFNα can lead to effective immune activation and attenuate tumor immune evasion, but persistent treatment has been shown to elicit immunosuppressive effects. Here, we identified an autophagy-dependent mechanism by which IFNα triggers tumor immune evasion by upregulating PD-L1 to suppress the antitumor activity of CD8+ T cells. Mechanistically, IFNα increased the transcription of TRIM14, which recruited the deubiquitinase USP14 to inhibit the autophagic degradation of PD-L1. USP14 removed K63-linked ubiquitin chains from PD-L1, impairing its recognition by the cargo receptor p62 (also known as SQSTM1) for subsequent autophagic degradation. Combining the USP14 inhibitor IU1 with IFNα and anti-CTLA4 treatment effectively suppressed tumor growth without significant toxicity. This work suggests a strategy for targeting selective autophagy to abolish PD-L1-mediated cancer immune evasion. Significance: IFNα-induced TRIM14 transcription suppresses antitumor immunity by recruiting USP14 to inhibit autophagic degradation of PD-L1, indicating that targeting this axis could be an effective immunotherapeutic approach for treating cancer.
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