Genetic insights into lung squamous cell carcinoma: how TP53 and CSMD3 co-mutations shape prognosis and immune response.

BACKGROUND

Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of lung cancer cases and is often associated with smoking and various environmental factors. The prognostic and immunologic implications of TP53 and CSMD3 co-mutations in LUSC remain poorly understood. This study aimed to investigate the role of TP53/CSMD3 co-mutations in LUSC using comprehensive bioinformatics analyses.

METHODS

Data from 487 LUSC patients were obtained from The Cancer Genome Atlas (TCGA) database, with external validation performed using the combined cohort. Patients were stratified into TP53/CSMD3 co-mutation, single-mutation, and wild-type (WT) groups. Prognostic analysis was conducted using Kaplan-Meier survival curves. Tumor mutational burden (TMB) was calculated, and immune cell infiltration was assessed using multiple algorithms. Differentially expressed genes (DEGs) between co-mutated and WT groups were identified, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A nomogram incorporating mutation status, gender, age, and tumor stage (T stage) was developed for individualized prognostic prediction.

RESULTS

The TP53/CSMD3 co-mutated group exhibited significantly better overall survival (OS) compared to single-mutation and WT groups. TMB scores were markedly higher in co-mutated patients, suggesting potential sensitivity to immune checkpoint inhibitors. Immune infiltration analysis revealed distinct profiles, including elevated CD8 T cells and reduced immunosuppressive components, in the co-mutation group. A total of 403 DEGs were identified between co-mutated and WT groups, with significant enrichment in immune-related pathways. Mechanistically, the co-mutation was associated with distinct downregulation of complement negative regulators (CFH/CFI), indicating complement hyperactivation independent of TMB. The constructed nomogram provided accurate individualized prognostic assessments.

CONCLUSIONS

The co-mutation of TP53 and CSMD3 identifies a distinct LUSC subtype with favorable survival, marked by high TMB and an immune-activated microenvironment. Beyond TMB-driven neoantigen generation, the significant downregulation of complement negative regulators (CFH/CFI) reveals an independent complement hyperactivation pathway associated with CSMD3 loss. The constructed nomogram provides accurate individualized survival prediction. These findings establish TP53/CSMD3 co-mutation as a promising prognostic biomarker and offer mechanistic insights for personalized immunotherapy strategies. Future prospective cohorts are warranted to validate its predictive value.