SSX1 and TRIM58 expression stratifies lung squamous cell carcinoma by tumor immune microenvironment characteristics and informs potential immunotherapy responsiveness.

[BACKGROUND] Lung squamous cell carcinoma (LUSC) remains a therapeutic challenge with limited biomarkers. The tumor immune microenvironment (TIME) is crucial for progression and immunotherapy response. Because SSX1 and TRIM58 emerged as significant independent prognostic factors, this study investigated their combined prognostic and immunological significance in LUSC.

[METHODS] Transcriptomic and clinical data from LUSC patients in The Cancer Genome Atlas (TCGA) were analyzed. A prognostic model was constructed, and consensus clustering was performed based on SSX1 and TRIM58 expression. Differences in survival, immune cell infiltration (assessed by CIBERSORT and ssGSEA), immune checkpoint expression, and ESTIMATE scores were evaluated. RT-qPCR on five paired LUSC and normal tissues validated key findings.

[RESULTS] Patients were stratified into two clusters: Cluster 1 (high SSX1/low TRIM58) and Cluster 2 (low SSX1/high TRIM58). RT-qPCR confirmed SSX1 upregulation and TRIM58 downregulation in tumors. Despite high TRIM58, Cluster 2 exhibited significantly poorer overall survival. This cluster demonstrated a more inflamed but immunosuppressive TIME, characterized by significantly increased infiltration of diverse immune cells (including activated T cells and M2 macrophages), higher Immune/ESTIMATE scores, and elevated expression of multiple immune checkpoint molecules (including PD-1, PD-L1, and CTLA-4).

[CONCLUSION] The expression of SSX1 and TRIM58 defines two distinct LUSC subtypes with contrasting TIME landscapes and clinical outcomes. The paradoxical combination of immune activation and poor survival in Cluster 2 highlights a potentially dysfunctional immune state. This two-gene signature could serve as a valuable biomarker for prognostic stratification and might offer insights into personalized immunotherapy strategies in LUSC.