AUTHOR=Shen Haixing , Zheng Qing , Wang Zhenyu , Zheng Daitian , Gong Zhenqi , Wang Huaiming , Sun Tianmiao , Pan Jie , Jin Yukai , Zheng Xiaohong , Wang Jingzhi , Zhang Jiongjiong 

TITLE=Breaking the heterogeneity barrier: a robust prognostic signature for survival stratification and immune profiling in triple-negative breast cancer

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1611917

DOI=10.3389/fimmu.2025.1611917

ISSN=1664-3224

ABSTRACT=BackgroundTriple-negative breast cancer (TNBC), a highly heterogeneous breast cancer subtype, poses significant challenges to human health. Intra-tumor heterogeneity (ITH) limits the reliability of conventional prognostic models.MethodsUsing multi-region RNA-seq, we quantified TNBC transcriptomic heterogeneity through an integrative heterogeneity score (IHS). After evaluating inter-patient heterogeneity (IPH) and ITH, prognostic and low-heterogeneity genes were identified and used to build a prognostic risk model with a random survival forest (RSF) algorithm. This model was combined with TNM staging into a nomogram for clinical applicability. We further revealed the distinct immune microenvironment features, somatic mutations, and chemotherapy responses between risk subgroups. Gene expression was validated via RT-qPCR.ResultsSpatial characterization uncovered substantial ITH, evidenced by sharp shifts in PAM50 subtypes and immune infiltration. Two low-heterogeneity biomarkers, CYP4B1 and GBP1, were identified to develop a robust prognostic signature with consistent predictive performance across 3- to 9-year survival endpoints (AUC > 0.6). The high-risk subgroup exhibited reduced immune infiltration, reduced immune checkpoint molecule expression, and poor immunotherapy response rates. Integration of the risk signature with TNM staging created a clinically practical nomogram with superior predictive accuracy (C-index >0.67). Therapeutic vulnerability profiling identified six targeted agents showing increased efficacy in high-risk patients. Dysregulation of signature genes was demonstrated in two TNBC cell lines.ConclusionsThis study established a transcriptomic heterogeneity-resilient prognostic model for TNBC, enabling precise survival stratification and immune microenvironment assessment. The integrative nomogram and risk-guided therapeutic predictions address clinical challenges in TNBC management, advancing personalized treatment strategies.