Immunogenic cell death-related classification reveals prognosis and effectiveness of immunotherapy in breast cancer

Sep 22, 2026

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Immunogenic cell death (ICD) is explored as a strategy to overcome limited biomarkers and drug targets in breast cancer. RNA-seq transcriptome data and clinical information for 943 patients from TCGA were used to derive ICD-related gene patterns, while an independent breast cancer cohort (GEO: GSE20685) validated results. Consensus clustering defined high- and low-ICD subtypes with distinct tumor microenvironment features. Prognostic models were built using ICD-correlated gene expression and a four-gene signature (ATG5, CD8A, CD8B, HSP90AA1) to predict outcomes and immunotherapy effectiveness.

LanguageEnglish

CategoryHealthcare

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Pages14

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Materials and methods

Datasets and statistical analysis

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Immunogenic cell death‑related classification reveals prognosis and effectiveness of immunotherapy in breast cancer Lei Zhu1, Yanmei Wu2, Haichun Zhao1, Zicheng Guo1, Biao Bo1 & Li Zheng1* Lack of specific biomarkers and effective drug targets constrains therapeutic research in breast cancer (BC) . In this regard, therapeutic modulation of damage‑associated molecular patterns (DAMPs)‑induced immunogenic cell death (ICD) may help improve the effect of immunotherapy in individuals with BC. The aim of this investigation was to develop biomarkers for ICD and to construct ICD‑related risk estimation models to predict prognosis and immunotherapy outcomes of BC. RNA‑ seq transcriptome information and medical data from individuals with BC (n = 943) were obtained from TCGA. Expression data from a separate BC cohort (GEO: GSE20685) were used for validation. We identified subtypes of high and low ICD gene expression by consensus clustering and assessed the connection between ICD subtypes and tumor microenvironment (TME) . In addition, different algorithms were used to construct ICD‑based prognostic models of BC. BC samples were categorized into subtypes of high and low ICD expression depending on the expression of genes correlated with ICD. The subtype of ICD high‑expression subtypes are correlated with poor prognosis in breast cancer, while ICD low‑expression subtypes may predict better clinical outcomes. We also created and verified a predictive signature model depending on four ICD‑related genes (ATG5, CD8A, CD8B, and HSP90AA1), which correlates with TME status and predicts clinical outcomes of BC patients. We highlight the connection of ICD subtypes with the dynamic evolution ofTME in BC and present a novel ICD‑based prognostic model of BC. In clinical practice, distinction of ICD subtype and assessment of ICD‑related biomarkers should help guide treatment planning and improve the effectiveness of tumor immunotherapy. Abbreviations BC DAMP DEGs GEO GO GSEA HLA HMGB1 ICD KEGG KM NK OD OS PRRsqRT-pcr SDS-PAGE Breast cancer Damage-associated molecular pattern Differentially Expressed Genes Gene Expression Omnibus Gene Ontology Gene Set Enrichment Analysis Human leukocyte antigen High mobility group proteins Immunogenic cell death Kyoto Encyclopedia of Genes and Genomes Kaplan–Meier Natural killer Optical density Overall survival Pathogen recognition receptors Quantitative real-time PCR SDS polyacrylamide gel electrophoresis 1Department of General Surgery, Panjin Liao-Oil Field Gem Flower Hospital, Panjin 124000, China. 2Department of Rheumatology and Immunology, Panjin Liao-Oil Field Gem Flower Hospital, Panjin 124000, China. *email: [zhengli_pj@163.com](zhengli_pj@163.com) [www. nature.com/scientificreports/](www. nature.com/scientificreports/) SNPs Single nucleotide polymorphisms TIDE Tumor Immune Dysfunction and Exclusion TME Tumor microenvironment Immunogenic cell death (ICD) is the mechanism by which, following a death stimulus, tumor cells transition from a non-immunogenic to an immunogenic state to induce an anti-tumor immune response1,2. ICD is characterized by the release of a cascade of signaling molecules referred to as damage-associated molecular patterns (DAMPs). These include calreticulin, which is found on the surface of cells, high mobility group proteins (HMGB1), which are secreted by cancerous cells, and ATP molecules and heat shock proteins (HSP70, HSP90), which are produced by cells undergoing death. DAMPs released during ICD can trigger a series of cytological responses by binding to pathogen recognition receptors (PRRs) in the dendritic cells’ surface, ultimately activating the innate and adaptive immune reactions3–5. The identification of ICD as a crucial mechanism mediating tumor-directed immune responses provided a new direction for precision tumor treatment6

FAQs

What was the goal of the study in breast cancer?

To develop ICD-related biomarkers and risk estimation models that predict prognosis and immunotherapy outcomes in breast cancer.

How were ICD subtypes defined?

By consensus clustering of ICD gene expression levels and evaluating associations with the tumor microenvironment.

What is the four-gene signature used for prediction?

A predictive signature based on ATG5, CD8A, CD8B, and HSP90AA1, linked to tumor microenvironment status and clinical outcomes.

Sep 22, 2026

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