Abstract B052: NF-κB-Inducing Kinase (NIK) in microglia promotes male-specific glioblastoma tumor pathogenesis

Abstract Introduction: Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor, characterized by profound therapy resistance and striking sex disparities, where males experience higher incidence and poorer survival than females. The GBM tumor microenvironment (TME) is highly immunosuppressive and dominated by microglia and infiltrated myeloid cells that promote tumor growth, invasion, and immune evasion. Our previous studies have established NF-κB–Inducing Kinase (NIK) as a central regulator of cancer cell metabolic reprogramming and macrophage immune-metabolic activation. However, how NIK influences the metabolic and signaling landscape of the brain immune TME, and whether these effects differ between sexes, remains unclear. Methods: We employed systemic and cell type-specific conditional knockout mouse models to identify the role of NIK in the GBM TME. Orthotopic implantation of syngeneic GL261 tumors was followed by survival, transcriptomic and immunohistochemical analyses to define how NIK loss impacts tumor growth, immune composition, and molecular signaling pathways. Results: Both systemic and microglia-specific NIK deletion markedly reduced GBM tumor size and progression. Interestingly, microglial NIK ablation significantly improved survival in male but not female hosts, indicating sex-dependent differences in NIK tumor-promoting functions. In contrast, astrocyte- and myeloid-specific NIK deletion failed to reproduce these effects, confirming a unique microglial-intrinsic mechanism. Transcriptomic analyses demonstrated that loss of microglial NIK altered extracellular matrix remodeling, cell migration, angiogenesis, and cytokine signaling - key processes related to GBM progression. Conclusion: Collectively, our findings highlight microglial NIK as a pivotal modulator of GBM progression that integrates immune-metabolic and tissue remodeling in a sex-dependent manner. Targeting NIK within microglia may suppress tumor growth and improve survival outcomes, particularly in males, underscoring the necessity of integrating sex as a biological variable in GBM research. Significance: This study uncovers a previously unrecognized microglial NIK-dependent signaling axis that drives brain tumor progression. These new insights advance our understanding of neuroimmune-tumor crosstalk and positions NIK as a promising therapeutic target for precision, cell type- and sex-informed GBM therapy. Citation Format: Hasara N. Abeygunaratne, Justin N. Keeney, Raquel Sitcheran. NF-κB-Inducing Kinase (NIK) in microglia promotes male-specific glioblastoma tumor pathogenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B052.