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Pro-inflammatory macrophages engage CXCR3 to elicit Integrated Stress Response-dependent metastatic potential in Triple-negative Breast Cancer

ABSTRACT: Triple-negative breast cancer (TNBC) is characterized by inflammatory myeloid infiltration and a high metastatic potential, yet how macrophage-derived signals are translated into tumor cell plasticity remain unclear. Here, through patient transcriptomic analyses, in vitro functional studies, and in vivo metastasis models, we identify the Integrated Stress Response (ISR) as a tumor cell-intrinsic pathway through which inflammatory macrophages drive metastatic competence. In breast cancer cohorts, ISR programs were enriched in TNBC, and associated with poor outcome and inflammatory macrophage infiltration. Functionally, the inflammatory macrophages secretome induced ISR-dependent invasion in TNBC cells. Mechanistically, CXCL10 emerged as a macrophage-derived cue necessary and sufficient to induce ISR activation and invasion via CXCR3. Finally, we demonstrate that tumor-intrinsic ISR activation sustains the TNBC metastatic dissemination in vivo. Together, these findings define a macrophage-CXCL10-CXCR3-ISR axis that fuels metastatic behavior in TNBC and identify this pathway as a potential node for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327254 | GEO | 2026/09/17

REPOSITORIES: GEO

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