Inflammatory macrophages promote metastatic potential in Triple-negative Breast Cancer through Integrated Stress Response signaling

Triple-negative Breast Cancer (TNBC) is characterized by inflammatory myeloid infiltration and a high metastatic potential, however, the mechanisms by which macrophage-derived signals govern tumor cell plasticity remain poorly understood. Here, through patient transcriptomic analyses, in vitro functional studies, and in vivo metastasis models, we identify the Integrated Stress Response (ISR) as a critical tumor cell-intrinsic pathway that translates inflammatory macrophage-derived cues into metastatic competence. In breast cancer clinical cohorts, ISR programs are enriched in TNBC and associate with poor outcome and inflammatory macrophage infiltration. Functionally, we show that the inflammatory macrophage secretome triggers ISR-dependent invasion in TNBC cells. Mechanistically, we identify CXCL10 as a macrophage-derived mediator necessary and sufficient to induce ISR activation and invasion through CXCR3 receptor. Finally, we demonstrate that tumor-intrinsic ISR signaling promotes TNBC metastatic dissemination in vivo. Together, our findings establish a macrophage-CXCL10-CXCR3-ISR signaling axis that fuels metastatic behavior in TNBC and identify this pathway as a potential node for therapeutic intervention.