Microenvironmental TRIM21 suppresses antitumor immunity in OSCC.

TRIM21, a member of the TRIM family of E3 ubiquitin ligases, is increasingly recognized for its role in immune regulation and has been implicated in various malignancies. However, its function in oral squamous cell carcinoma (OSCC) remains undefined. Here, we show that TRIM21 is significantly upregulated in human OSCC tissues and serves as an independent adverse prognostic factor for overall survival. Consistently, systemic Trim21 deficiency significantly suppressed OSCC tumorigenesis in a 4-nitroquinoline 1-oxide-induced oral carcinogenesis model. In contrast, TRIM21 knockdown did not significantly affect OSCC cell proliferation or migration in vitro, suggesting that its tumor-promoting effects may not be primarily mediated by the tumor cell-intrinsic behaviors examined under these conditions. Supporting this notion, bioinformatic analyses revealed strong associations between TRIM21 expression, immune checkpoint-related pathways, and immune cell infiltration. To further assess the contribution of TRIM21 in the tumor microenvironment in vivo, we established an orthotopic tongue allograft model and found that microenvironmental Trim21 deficiency markedly suppressed tumor growth. CyTOF and mIHC analyses further showed that microenvironmental Trim21 deficiency reduced PD-L1 expression on conventional dendritic cells (cDCs) and enhanced the cytotoxic activity of tumor-infiltrating CD8+ T cells. Collectively, TRIM21 promotes OSCC progression predominantly through modulation of the tumor immune microenvironment. This role may involve supporting an immunosuppressive cDC phenotype and restraining CD8+ T-cell-mediated antitumor immunity. TRIM21 may therefore serve as an independent prognostic biomarker and a potential therapeutic target in OSCC, with possible relevance to combination strategies involving immune checkpoint blockade.