Tumor microenvironment transcriptional activity enables robust stratification of chemotherapy response in triple-negative breast cancer

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. • TmS subtypes outperform existing TNBC subtypes in predicting chemotherapy response • Stromal barriers and immune exclusion define treatment-resistant low-TmS tumors • Population-specific immune patterns distinguish Asian and European low-TmS tumors • ECM signatures represent conserved therapeutic targets across all populations Dai et al. demonstrate that tumor-specific total mRNA expression (TmS) outperforms existing classifications in stratifying triple-negative breast cancer chemotherapy responses across diverse populations. This deconvolution approach reveals population-specific tumor microenvironment programs and identifies extracellular matrix targeting as a therapeutic strategy for patients with low-TmS.