Multicohort Construction, Immune Landscape Analysis, and PCOLCE2 Functional Validation of an Inflammation‐Related Prognostic Model in Colorectal Cancer

Vollständiger Abstract

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ABSTRACT Colorectal cancer (CRC) prognosis remains challenging due to tumor heterogeneity and immune evasion driven by aberrant inflammatory signaling, and robust multicohort validated prognostic tools with clear therapeutic implications are still lacking. To address this gap, we integrated five independent CRC cohorts (TCGA, GSE17536, GSE17537, GSE29621, and GSE38832; n = 931) and applied single‐sample gene set enrichment analysis (ssGSEA) across 15 inflammation‐related signaling pathways to construct a prognostic risk score model via multicohort Cox regression and LASSO‐Cox regression. The immune landscape was systematically characterized using immune infiltration algorithms, Cancer Immunity Cycle scoring, CellChat analysis, and single‐cell RNA sequencing (scRNA‐seq) data (GSE166555). The functional role of the candidate gene PCOLCE2 was further validated through in vitro migration and adhesion assays, and confirmed in a syngeneic C57BL/6 mouse subcutaneous tumor model in which MC38‐shPCOLCE2 cells were inoculated and treated with anti‐PD‐1 antibody (200 μg per mouse, every 3 days) alone or in combination to evaluate the synergistic antitumor effect. The resulting 12‐gene inflammation‐related risk model achieved robust survival stratification across all five independent cohorts, with AUC values of 0.70–0.85 and C‐indices consistently outperforming existing prognostic models, demonstrating strong generalizability as a clinical prognostic tool. High‐risk patients exhibited significantly worse overall survival ( p < 0.001), an immunosuppressive tumor microenvironment, and elevated pro‐stromal remodeling signaling, patterns that were corroborated by single‐cell resolution analysis. Mechanistically, PCOLCE2 knockdown suppressed CRC cell migration and enhanced matrix adhesion in vitro. Critically, in vivo combination of PCOLCE2 knockdown with PD‐1 blockade produced a synergistic antitumor effect superior to either monotherapy ( p < 0.01), highlighting PCOLCE2 as a promising therapeutic target to enhance immunotherapy response. Together, these findings present a clinically actionable, multicohort validated inflammation‐related prognostic model for CRC risk stratification, and position PCOLCE2 as a driver of invasion and immune evasion whose combination with PD‐1 blockade offers a rational therapeutic strategy to improve immunotherapy efficacy in high‐risk CRC patients.