Abstract B060: Chemotherapy-Induced Astrocyte Senescence Drives Neutrophil Extracellular Trap–Mediated Awakening of Dormant DTCs and Brain Metastatic Relapse in Breast Cancer

Abstract Dormant disseminated tumor cells (DTCs) are key drivers of late metastatic relapse, but their biology in breast cancer brain metastasis is still not well understood. In this study, we show that chemotherapy can “wake up” dormant DTCs via neutrophil extracellular trap (NET) formation induced by senescent astrocytes. Senescent astrocytes release IL-6, which promotes NETosis, and NET-associated DNA then binds to the tumor cell surface receptor , activating NF-kB signaling and facilitating escape from dormancy. Interrupting this pathway with a surface receptor-neutralizing antibody markedly reduces DTC reactivation and brain metastatic outgrowth without impairing the antitumor efficacy of chemotherapy. These results identify a previously unappreciated astrocyte senescence–NET axis that connects chemotherapy-induced brain microenvironment damage to metastatic recurrence and suggests a potential therapeutic strategy to prevent relapse in breast cancer patients with brain metastasis. Citation Format: Shangheng Shi. Chemotherapy-Induced Astrocyte Senescence Drives Neutrophil Extracellular Trap–Mediated Awakening of Dormant DTCs and Brain Metastatic Relapse in Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B060.