TRIM29 suppresses malignant progression in lung squamous cell carcinoma by shaping an immunosuppressive tumor microenvironment

TRIM29 (tripartite motif containing 29) is a multifunctional protein with context-dependent roles in cancer, acting as either an oncogene or a tumor suppressor. In this study, we investigated the role of TRIM29 in lung squamous cell carcinoma (LUSC) and its impact on the tumor microenvironment. We found that TRIM29 is highly expressed in early-stage LUSC, primarily due to promoter hypomethylation and copy number amplification. High TRIM29 expression was significantly associated with improved overall survival, disease-specific survival, and progression-free survival in LUSC patients. However, TRIM29 did not remain an independent prognostic factor after adjusting for clinical covariates, as well as tumor purity and keratinization-related programs. Functionally, TRIM29 suppressed tumor cell proliferation, migration, and epithelial-mesenchymal transition in vitro, and inhibited tumor growth and metastasis in a syngeneic mouse model. Mechanistically, TRIM29 activated tumor-suppressive pathways (e.g., p53) and epithelial markers (e.g., KRT5), while repressing oncogenic pathways (e.g., KRAS, IL6-JAK-STAT3). Unadjusted bulk transcriptome analyses suggested that TRIM29-high tumors exhibit an immune-cold phenotype with reduced immune infiltration. However, these associations attenuated after adjustment for tumor purity and keratinization programs. Notably, the syngeneic model provided orthogonal evidence that TRIM29 overexpression can decrease intratumoral CD8 + T-cell infiltration. Protein-protein interaction analysis identified KRT5 and TRAT1 as key interactors, suggesting that TRIM29 may preserve squamous differentiation while simultaneously attenuating anti-tumor immunity. Our findings support a context-dependent dual role of TRIM29 in LUSC, where it combines tumor-intrinsic suppression of malignant progression with potential remodeling of the tumor microenvironment. This study provides new insights into the complex role of TRIM29 in LUSC and underscores its potential as a therapeutic target, warranting further validation in cell-type–resolved and clinically annotated cohorts.