Abstract Background: Glioblastoma (GBM) is the most common aggressive primary brain tumor, with a median overall survival (OS) of ≈15-18 months despite standard of care (SOC). Aging is a major negative prognostic factor, with older adults showing worse OS. Senescent cells accumulate with age and contribute to poorer outcomes. Senolytics clear senescent cells and may improve responses in older hosts. While tumor-intrinsic molecular features appear age-independent, the aging brain microenvironment impact on GBM progression and immunity remains unclear. Objective: To define age-associated senescence patterns in tumor core and peritumoral (PT) brain in GBM patients and mouse models and assess whether senolytic enhance treatment responses in aged syngeneic and humanized GBM models. Methods: MRI-guided tumor core and PT biopsies from GBM patients (65 vs. ≥65) underwent transcriptomic and single-cell analyses to assess age-related neuro-immune and senescence changes. Senescence across tumor regions was examined in young (7-9 weeks) and aged (97-104 weeks) C57BL/6 and INK-ATTAC mice with intracranial SB28 tumors (n=5/group). Flow cytometry quantified β-gal+ senescent populations among neurons, astrocytes, oligodendrocytes, microglia, and immune infiltrates from tumor core and extratumoral brain. Mice received brain radiation, anti-PD-1, and IDO enzyme inhibition, alone ± senolytics (dasatinib+quercetin) or AP compound-induced clearance p16INK4A+ senescent cells. A human GBM aging model was developed by depleting CD4+, CD8+, CD19+, and NK1.1+ cells in young and aged C57BL/6 mice, prior to patient-derived GBM43 (PDX) intracranial engraftment, followed by SOC radiotherapy + temozolomide ± senolytics. Results: Transcriptomic profiling showed minimal age-related changes in tumor core but marked alterations in older PT tissues. Aged PT microglia exhibited a senescent phenotype with an upregulation of senescence-associated secretory phenotype (SASP) genes. Senolytics or AP compound significantly reduced extratumoral β-gal+ microglia and synergized with radio-immunotherapy to extend OS in aged mice (p0.05). In the humanized immunodepleted GBM43 PDX model, young and aged mice developed tumors, with faster mortality in older hosts. Therapeutic responses to SOC ± senolytics are ongoing. Conclusions: The PT brain is a key site of age-dependent immune dysfunction in GBM. Senescent microglia may create an immunosuppressive niche that limits the immunotherapy efficacy in older adults. Senolytics may restore treatment efficacy and improve outcomes in older GBM hosts. We developed a novel immunodepleted GBM PDX model to mechanistically evaluate the role of aging in human tumor progression and therapy resistance. Keywords: glioblastoma, peritumoral brain, aging, immunotherapy, senescence, microglia Citation Format: Manon Penco-Campillo, Olaya de Dios, Megan Callender, Kristen L. Lauing, Oluwatomilayo Odum, Taylor Koch, Lijie Zhai, Vikram C. Prabhu, Douglas E. Anderson, Anand V. Germanwala, Jigisha P. Thakkar, Prashant Bommi, Pilar Sanchez-Gomez, Frederick Varn, Derek Wainwright. Age-dependent neuro-immune changes in glioblastoma shape therapeutic response and reveal senescent microglia as a targetable vulnerability abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6826.
Penco-Campillo et al. (2026) studied this question.