Cell Senescence-Related Genes As Biomarkers for Prognosis and Immunotherapeutic Response in Colon Cancer

Colon adenocarcinoma (COAD) stands out as the most prevalent malignancy diagnosed within the gastrointestinal tract, bearing substantial incidence and mortality rates. The processes of ageing and senescence intricately intertwine with tumorigenesis and immune regulation, concurrently exerting influence on the remodelling of the tumor microenvironment (TME). This phenomenon, in turn, significantly impacts the efficacy of immunotherapeutic interventions. Despite this awareness, the comprehensive understanding of the intricate interplay between cellular senescence and TME in the context of COAD remains elusive. Further inquiry is imperative to comprehensively gauge the relevance of cellular senescence-related genes (CSGs) in the realms of immune infiltration and the prognostication of COAD. Differentially expressed cell senescence-related genes (DE-CSGs) within COAD tumors and normal specimens were discerned through analysis of the TCGA-COAD dataset. Leveraging univariate, LASSO, and multivariate Cox regression analyses, we formulated a prognostic risk signature. Subsequent validation utilised two independent GEO datasets. Furthermore, a nomogram was devised to gauge the prognostic significance of this signature. Additionally, the immune landscape of the Cell Senescence-related Signature (CSS) was characterised using CIBERSORT and TIMER algorithms. The expression levels of CSGs were quantified through RT-PCR in COAD specimens. Drawing upon mRNA expression profiles of 191 DE-CSGs, we successfully established a 9-gene CSS, demonstrating its autonomy as a prognostic determinant for COAD patients. Those assigned high-risk scores exhibited an immunosuppressive phenotype, marked by elevated proportions of resting CD4+memory T cells and macrophages M0, correlating with diminished overall survival. Subsequent analyses uncovered that the amalgamation of CSS with the expression profiles of immune checkpoint key genes effectively predicted patient prognosis. Furthermore, patients with low-risk scores demonstrated a potential association with more favourable therapeutic outcomes in the context of immunotherapy. This study has culminated in the development of a prognostic risk signature grounded in cell senescence-related genes for COAD. We posit that the CSS plays a regulatory role in immune infiltration, emerging as a robust biomarker for prognosis and a predictive indicator for immunotherapeutic responsiveness within the COAD landscape.