PURPOSE: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. While GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation Experimental Design: Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naive myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immune competent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors. RESULTS: GBM-derived interleukin-6 (IL-6) was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. Inhibition of IL-6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL-6 therapy proved to be CD8+ T cell dependent, and the anti-tumor activity was additive with that provided by programmed death-1 (PD-1) targeted immunotherapy. CONCLUSIONS: Our findings suggest that disruption of IL-6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated anti-tumor responses against GBM.