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Interferon-Stimulated Neutrophils Impair Breast Cancer Response to Immunotherapy and Disrupt Immunological Memory

ABSTRACT: Despite durable remissions observed in a subset of cancer patients treated with immunotherapy, the majority remain unresponsive, underscoring the need for predictive biomarkers and novel therapeutic targets. In this study, we integrated single-cell RNA sequencing, spatial transcriptomics, and conditional knockout mouse models to uncover a conserved neutrophil interferon (IFN)-stimulated gene signature that predicts responsiveness to anti-PD1 therapy. We demonstrate that early reductions in neutrophil abundance and neutrophil IFN responses are strongly associated with therapeutic efficacy, while the spatial exclusion of neutrophils from tertiary lymphoid structures emerges as a hallmark of successful treatment. Furthermore, our findings reveal that neutrophil IFN signaling is pivotal in mediating resistance to therapy and in impairing the development of durable immunological memory. These findings offer insights into the interplay between neutrophil IFN signaling and adaptive immunity, providing a foundation for developing bloodborne biomarkers and combinatorial strategies to enhance the efficacy of immune checkpoint blockade therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE301336 | GEO | 2026/05/22

REPOSITORIES: GEO

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