High-Density Type I Collagen Promotes IFN-γ⁺ CD8⁺ T Cell Exhaustion via SAT1-ASS1-Mediated Glutamine Accumulation and Ferroptosis in Triple-Negative Breast Cancer.

Authors

Jinyan Wang, Shuangyue Pan, Lu Bai, Bin Li, Tiantian Liu, Jianing Cao, Mengdi Yang, Heda Zhang, Duancheng Guo, Wenxiang Zhi, Zhonghua Tao, Xichun Hu

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77879. Sep 27, 2026. Epub Sep 27, 2026.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by poor prognosis because of a lack of effective therapeutic agents. Changes in extracellular matrix (ECM) composition, particularly type I collagen density, significantly influence crucial cellular activities. However, the association between type I collagen density and TNBC progression remains unclear. This study finds that type I collagen density and mechanical characteristics of lesions predict the pathological grade and malignant progression of TNBC patients. The results of transcriptomics and metabolomics studies suggest that high-density type I collagen promotes TNBC ferroptosis. Further in vitro experiments indicate that high-density type I collagen promotes ferroptosis in TNBC cells through spermidine/spermine N1-acetyltransferase 1 (SAT1)/argininosuccinate synthase (ASS1)-induced glutamine (Gln) accumulation. Moreover, in vitro co-culture and in vivo experiments reveal that high-density type I collagen increases the uptake of Gln in TNBC cells, leading to Gln deprivation of IFN-γ⁺ CD8⁺ T cells in the tumor microenvironment, resulting in higher level of immunosuppression. Combination of ferrostatin 1 and anti-PD-1 therapy reverses high-density collagen-induced tumor progression of TNBC. The clinical samples further verify the role of collagen density in TNBC. This study reveals that high-density type I collagen participates in TNBC progression partly through immunosuppression induced by Gln accumulation-related ferroptosis.

PMID:
42801687
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.

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