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Arginine deprivation reshapes tumor and immune transcriptional programs and potentiates IFNγ–JAK–STAT signaling in 4T1 murine breast tumors

ABSTRACT: Arginine availability is a key metabolic regulator of tumor and immune cell function. We performed single-cell RNA sequencing of orthotopic 4T1 murine triple-negative breast tumors to define cell type–specific transcriptional adaptations to arginine deprivation. We demonstrate that arginine depletion induces widespread transcriptional reprogramming across both stromal and immune compartments, with particularly pronounced effects in cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). In tumor cells, cancer cell–intrinsic (via Ass1 knockdown), systemic (via an arginine-free diet), or combined restriction of arginine availability resulted in elevated inflammatory responses, including activation of interferon-alpha (IFNα) and interferon-gamma (IFNγ) signaling, and, to a lesser extent, IL6–JAK–STAT3 signaling. These changes, mediated by tumor microenvironment (TME)–supportive interactions, sustain tumor cell survival under arginine-deprived conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE310301 | GEO | 2026/01/14

REPOSITORIES: GEO

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