The non-apoptotic functions of Fas signaling have been proposed to play significantly promoting roles in tumorigenesis and tumor progression.Then, the development of effective cancer therapies targeting the Fas signaling attracts much attention now.Here we found that the breast cancer cells with constitutive Fas expression were resistant to agonistic anti-Fas antibody (Jo2)-induced or Fas ligand cross-linking-induced apoptosis.And, higher expression of Fas in human breast cancer tissues was significantly correlated with poorer prognosis of breast cancer patients.These data raise the intriguing possibility that whether Fas signaling could accelerate breast cancer progression and, therapeutically, whether blockade of Fas signaling in breast cancer could suppress tumor progression.Using mouse mammary cancer cells 4T1 orthotopic xenograft model, we found that blockade of Fas signaling or silencing of Fas expression in 4T1 cancer cells markedly reduced tumor growth and inhibited tumor metastasis in vivo, accordingly prolonged survival of tumorbearing mice.Mechanistically, blockade of Fas signaling in cancer cells significantly decreased systemic or local recruitment of MDSCs in vivo.Furthermore, blockade of Fas signaling markedly reduced IL-6, PGE2 production by impairing p-p38, NFκB pathways, and administration of COX-2 inhibitor and anti-IL-6 antibody significantly reduced MDSCs accumulation in vivo.Therefore, blockade of Fas signaling can suppress breast cancer progression by inhibiting proinflammatory cytokine production and MDSCs accumulation, indicating that Fas signaling-initiated cancer-related inflammation in breast cancer cells may be potential target to be interfered for treatment of breast cancer.