Tumor Microenvironment Transcriptional Activity Enables Robust Stratification of Chemotherapy Response in Triple-Negative Breast Cancer

Authors

Yaoyi Dai
Xiaoxi Pan
Shuai Guo
Shuangxi Ji
Shaolong Cao
Matthew D Montierth
Yujie Jiang
Jeffrey T Chang
Leming Shi
Shabnam Shalapour
Gloria V Echeverria
Lucy Yates
Johan Staaf
Bora Lim
Yinyin Yuan
Wenyi Wang

Language

English

Publication Date

2-17-2026

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2026.102610

PMID

41707645

PMCID

PMC12923974

PubMedCentral® Posted Date

2-17-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Triple-negative breast cancer (TNBC) exhibits heterogeneous treatment responses, yet molecular subtypes based on predefined biological pathways show limited prognostic value. We introduce tumor-specific total mRNA expression (TmS), a pathway-agnostic deconvolution metric derived from matched RNA/DNA sequencing, as a robust stratification tool. Analyzing 575 TNBC patients across Western and East Asian populations, TmS outperforms established subtypes in predicting chemotherapy outcomes, stratifying patients into high TmS with favorable prognosis and low TmS with poor prognosis. Stromal enrichment with immune exclusion emerges as a universal feature of chemotherapy-resistant low-TmS tumors across all cohorts. Population-specific features distinguish Asian cohorts: high-TmS tumors exhibit cell cycle-driven proliferation programs, and low-TmS tumors display immune dysfunction with memory B cell enrichment and divergent RAS/mitogen-activated protein kinase (MAPK) activation, compared to Western populations. Despite these differences, extracellular matrix organization represents a conserved therapeutic vulnerability in treatment-resistant low-TmS patients. TmS provides a unifying framework for dissecting TNBC heterogeneity and enabling precision therapy across diverse populations.

Keywords

Humans, Triple Negative Breast Neoplasms, Female, Tumor Microenvironment, Gene Expression Regulation, Neoplastic, Prognosis, Drug Resistance, Neoplasm, Transcription, Genetic, RNA, Messenger, transcriptome plasticity, transcriptomic deconvolution, prognostic stratification, tumor microenvironment

Published Open-Access

yes

Recommended Citation

Dai, Yaoyi; Pan, Xiaoxi; Guo, Shuai; et al., "Tumor Microenvironment Transcriptional Activity Enables Robust Stratification of Chemotherapy Response in Triple-Negative Breast Cancer" (2026). Faculty, Staff and Student Publications. 6148.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6148