High‐Density Type I Collagen Promotes IFN‐γ ⁺ CD8 ⁺ T Cell Exhaustion via SAT1‐ASS1‐Mediated Glutamine Accumulation and Ferroptosis in Triple‐Negati

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.