Introduction: Exceptional responders refer to the rare subset of patients who derive extraordinary benefits from a therapy compared to most treated patients. Understanding the basis for such responses represents a key pillar in the framework of precision medicine. Objective: Here, we examine the molecular basis underlying exceptional responses in glioblastoma patients who underwent concurrent radiation and temozolomide (TMZ) therapy. Methods: mRNA profiles derived from clinically annotated glioblastoma specimens were analyzed by Single sample gene set enrichment (ssGSEA) and Gene Cluster Expression Summary Score (GCESS). Key results were confirmed using cell-based assays and murine glioblastoma models. Results: Integrated, multi-platform analyses of RNA profiles derived from clinically annotated glioblastoma samples revealed decreased accumulation of microglia/macrophages in the tumor microenvironment of exceptional responders. Further analysis revealed that glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) activate a STAT3-MYC signaling axis in glioblastoma cells. This signaling facilitated glioblastoma transition into stem cell states that confer enhanced tumorigenicity as well as resistance to the TMZ. Pharmacologic inhibition or genetic inactivation of a myeloid cell restricted isoform of PI3K, PI3K-gamma, disrupted this signaling axis by suppressing microglia/macrophage accumulation and IL11 secretion in the glioblastoma microenvironment. Mirroring the clinical outcome of exceptional responders, PI3K-gamma inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3K-gamma in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Conclusions: Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3K-gamma inhibition as a glioblastoma therapy.