Work

An immunogenic cell death-related classification for prognostic stratification and immunotherapy response prediction in proficient mismatch repair/microsatellite stable colorectal cancer

Year: 2026

Type: article

Abstract: Background: Proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) constitutes the predominant molecular subgroup of CRC and usually shows limited benefit from immune checkpoint blockade. This study aimed to characterize immunogenic cell death (ICD)-associated transcriptomic patterns and develop an ICD-related prognostic model for pMMR/MSS CRC. Methods: Public gene-expression profiles and clinical annotations were retrieved from the Gene Expression Omnibus (GEO). The GSE39582-pMMR cohort was used for subtype identification and model development (n=459), and eligible pMMR/MSS cases from GSE143985 and GSE92921 were combined for external validation (n=132). Thirty-four ICD-related genes were used for consensus clustering. Differential expression analysis, functional enrichment analysis, Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE), single-sample gene set enrichment analysis, immune checkpoint and human leukocyte antigen (HLA) assessment, Tumor Immune Dysfunction and Exclusion (TIDE) prediction, Kaplan-Meier analysis, least absolute shrinkage and selection operator (LASSO) Cox regression, time-dependent receiver operating characteristic (ROC) analysis, and Cox proportional hazards models were applied. Results: Consensus clustering divided the GSE39582-pMMR cohort into ICD-high (n=155) and ICD-low (n=304) subtypes. The ICD-high subtype showed higher immune and stromal scores, lower tumor purity, broader immune-cell infiltration, and increased expression of checkpoint and HLA genes, although overall survival did not differ significantly between subtypes. Subtype-related genes were enriched in immune response, leukocyte migration, chemokine and complement activity, adhesion, and extracellular matrix pathways. A seven-gene model consisting of CASP1 , IL1R1 , IL6 , MYD88 , NT5E , P2RX7 , and PIK3CA stratified patients with significantly different overall survival in the development cohort and showed an unfavorable disease-free survival trend in the external validation cohort. Higher risk scores were associated with myeloid immunosuppressive infiltration and TIDE-defined non-response. Multivariate Cox analysis identified the risk score as an independent prognostic factor. Conclusions: ICD-associated transcriptional patterns identified immune-distinct subtypes in pMMR/MSS CRC and yielded a prognostic signature associated with survival and predicted immunotherapy response. The ICD-high subtype showed an immune-infiltrated but immunosuppression-associated phenotype, supporting further investigation of ICD-related models for risk stratification and treatment-response estimation in pMMR/MSS CRC.

Source: Journal of Gastrointestinal Oncology

DOI: 10.21037/jgo-2026-0748