An immunogenic cell death-related classification for prognostic stratification and immunotherapy response prediction in proficient mismatch repair/microsatellite stable colorectal cancer.
- 1Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
Abstract
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. 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. 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. 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.
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BibTeX
@article{he2026immunogenic,
title = {{An immunogenic cell death-related classification for prognostic stratification and immunotherapy response prediction in proficient mismatch repair/microsatellite stable colorectal cancer.}},
author = {Jia He and Jinxiu Qu and Yuan Zhao and Pinxu Ge and Shijie Yu and Jiqiang Xu and Xin Wang and Benqiang Rao},
journal = {Journal of gastrointestinal oncology},
year = {2026},
month = sep,
doi = {10.21037/jgo-2026-0748},
url = {https://europepmc.org/article/MED/42996609},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - An immunogenic cell death-related classification for prognostic stratification and immunotherapy response prediction in proficient mismatch repair/microsatellite stable colorectal cancer.
AU - Jia He
AU - Jinxiu Qu
AU - Yuan Zhao
AU - Pinxu Ge
AU - Shijie Yu
AU - Jiqiang Xu
AU - Xin Wang
AU - Benqiang Rao
PY - 2026
DA - 2026/09/29
JO - Journal of gastrointestinal oncology
DO - 10.21037/jgo-2026-0748
UR - https://europepmc.org/article/MED/42996609
AB - 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. 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. 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. 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.
SN - 2078-6891
SN - 2219-679X
ER -