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Background Glioblastoma (GBM) is an aggressive malignant brain tumor where median survival is approximately 15 months after best available multimodal treatment. Recurrence is inevitable, largely due to O6 methylguanine DNA methyltransferase (MGMT) that renders the tumors resistant to temozolomide (TMZ). We hypothesized that pretreatment with bortezomib (BTZ) 48 hours prior to TMZ to deplete MGMT levels would be safe and tolerated by patients with recurrent GBM harboring unmethylated MGMT promoter. The secondary objective was to investigate whether 26S proteasome blockade may enhance differentiation of cytotoxic immune subsets to impact treatment responses measured by radiological criteria and clinical outcomes. Methods Ten patients received intravenous BTZ 1.3 mg/m2 on days 1, 4, and 7 during each 4th weekly TMZ‐chemotherapy starting on day 3 and escalated from 150 mg/m2 per oral 5 days/wk via 175 to 200 mg/m2 in cycles 1, 2, and 3, respectively. Adverse events and quality of life were evaluated by CTCAE and EQ‐5D‐5L questionnaire, and immunological biomarkers evaluated by flow cytometry and Luminex enzyme‐linked immunosorbent assay. Results Sequential BTZ + TMZ therapy was safe and well tolerated. Pain and performance of daily activities had greatest impact on patients' self‐reported quality of life and were inversely correlated with Karnofsky performance status. Patients segregated a priori into three groups, where group 1 displayed stable clinical symptoms and/or slower magnetic resonance imaging radiological progression, expanded CD4+ effector T‐cells that attenuated cytotoxic T‐lymphocyte associated protein‐4 and PD‐1 expression and secreted interferon γ and tumor necrosis factor α in situ and ex vivo upon stimulation with PMA/ionomycin. In contrast, rapidly progressing group 2 patients exhibited tolerised T‐cell phenotypes characterized by fourfold to sixfold higher interleukin 4 (IL‐4) and IL‐10 Th‐2 cytokines after BTZ + TMZ treatment, where group 3 patients exhibited intermediate clinical/radiological responses. Conclusion Sequential BTZ + TMZ treatment is safe and promotes Th1‐driven immunological responses in selected patients with improved clinical outcomes (Clinicaltrial.gov (NCT03643549))., Schematic of trial schedule. A, Timeline showing BORTEM‐17 treatment regimen. Bortezomib administered intravenous at days 1, 4, and 7 (48 hours pretreatment to deplete MGMT protein) before target TMZ 200 mg/m2 dose for 5 days (from and including days 3‐7), repeated in six cycles. In n = 3 patients per each dose 150 vs 175 vs 200 mg/m2 TMZ in dose pathfinding, safety evaluation. Clinical chemistry for renal, hepatic, and bone marrow monitoring for toxicity based on CTCAE v. 4.03. MRI tumor monitoring radiological response assessment based on RANO criteria. Rationale for sequential treatment schedule based on preclinical data. B, sequential administration in BORTEM‐17 clinical trial vs (C) previous studies where BTZ on days 1, 4, 8, and 11 was given concomitantly with TMZ from day 1 to 5, when MGMT levels were high. Dashed boxes mark days when TMZ doses might be more effective, (B) all five doses vs (C) three doses every month. BTZ, bortezomib; CBC Diff, complete blood count with differential test; CMP, comprehensive metabolic panel; KPS, Karnofsky performance score; LFT, liver function test; MGMT, O6‐methyl guanine DNA methyltransferase; MRI, magnetic resonance imaging; NANO, neurologic assessment in neuro‐oncology; QoL, quality of life; TMZ, temozolomide.