TRIM59 通过泛素-蛋白酶体降解 IRF3 促进肺腺癌的免疫逃逸和肿瘤进展

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, with immune evasion being a key driver of treatment resistance and poor prognosis. The tripartite motif-containing (TRIM) family of E3 ubiquitin ligases plays critical roles in regulating tumor immunity, but the functional relevance and molecular mechanisms of most TRIM members in LUAD remain elusive.

Here, we integrated multi-omics analyses with functional experiments to systematically investigate the prognostic value and immunoregulatory role of TRIM family in LUAD.

We identified TRIM59 as an independent poor prognostic factor, with its high expression correlating with an immunosuppressive tumor microenvironment (TME).

Mechanistically, TRIM59 interacts with interferon regulatory factor 3 (IRF3) and promotes its ubiquitination and proteasomal degradation, thereby inhibiting the IRF3-STING pathway and downstream anti-tumor interferon production.

Single-cell analyses revealed cell-type-specific functions of IRF3: in tumor cells, IRF3 may suppresses immune-activating gene expression and modulates proliferation; in tumor-infiltrating T/NK cells, IRF3 negatively regulates pro-inflammatory signaling. Collectively, our findings establish the TRIM59-IRF3 axis as a novel regulatory pathway driving LUAD immune evasion, providing a promising prognostic biomarker and therapeutic target for enhancing immunotherapy efficacy.