Single-cell and spatial mapping reveals GCLC+ mesenchymal tumor cells linked with favorable outcomes in TNBC

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Abstract
Oxidative stress response (OSR) is suggested as a therapeutic target in triple negative breast cancer (TNBC). However, the cell type specificity and spatial distribution of OSR genes and proteins remain poorly defined. We re-analyzed public datasets, demostrating high OSR gene expression in TNBC tumor cells. We generated a multiplex immunofluorescence dataset of 345 TNBC samples that showed OSR proteins GCLC and NQO1 are differentially expressed across tumor, immune, and stromal cells, and elevated in inflamed regions. We identified a mesenchymal-like tumor cell state characterized by co-expression of GCLC and vimentin (GCLC⁺VIM⁺), with increased proliferation and reduced anastasis-associated signatures, suggesting a vulnerability to chemotherapy. Consistently, TNBC cell lines with higher GCLC expression showed increased sensitivity to cisplatin. Moreover, patients with higher proportions of GCLC⁺VIM⁺ tumor cells had longer overall survival. Our findings indicate that OSR proteins are expressed in spatially and phenotypically distinct tumor microenvironments, and that the GCLC⁺VIM⁺ tumor cell state is associated with favorable outcomes in TNBC.