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Many patients with breast cancer have a poor prognosis with limited therapeutic options. Here, we investigated the potential of chemo-immunogenic therapy as an avenue of treatment. We utilized two syngeneic mouse mammary tumor models, 4T1 and E0771, to examine the chemo-immunogenic potential of cyclophosphamide and the mechanistic contributions of cyclophosphamide-activated type-I IFN signaling to therapeutic activity. Chemically activated cyclophosphamide induced robust IFNα/β receptor-1–dependent signaling linked to hundreds of IFN-stimulated gene responses in both cell lines. Furthermore, in 4T1 tumors, cyclophosphamide given on a medium-dose, 6-day intermittent metronomic schedule induced strong IFN signaling but comparatively weak immune cell infiltration associated with long-term tumor growth stasis. Induction of IFN signaling was somewhat weaker in E0771 tumors but was followed by widespread downstream gene responses, robust immune cell infiltration, and extensive, prolonged tumor regression. The immune dependence of these effective antitumor responses was established by CD8 T-cell immunodepletion, which blocked cyclophosphamide-induced E0771 tumor regression and led to tumor stasis followed by regrowth. Strikingly, IFNα/β receptor-1 antibody blockade was even more effective in preventing E0771 immune cell infiltration and blocked the major tumor regression induced by cyclophosphamide treatment. Type-I IFN signaling is thus essential for the robust chemo-immunogenic response of these tumors to cyclophosphamide administered on a metronomic schedule. Significance: Many patients with breast cancer have few therapeutic options. We show that cyclophosphamide treatment induces extensive tumor regression in a syngeneic mouse model of breast cancer via a chemo-immunogenic mechanism linked to type-I IFN production. Our findings establish that IFN signaling is essential for the robust antitumor actions of cyclophosphamide and suggest that treatment resistance may stem from silencing the IFN pathway. This suggests a new avenue for improving breast cancer treatment efficacy.

Type-I Interferon Signaling Is Essential for Robust Metronomic Chemo-Immunogenic Tumor Regression in Murine Breast Cancer