Abstract 7457: IL-33-mediated control of myeloid immunity in glioblastoma progression

Abstract Glioblastoma (GB) is the most lethal primary brain cancer in adults, characterized by a profoundly immunosuppressive microenvironment dominated by tumor-associated macrophages and microglia (TAMs). We previously identified Interleukin-33 (IL-33), a dual-function cytokine with nuclear and extracellular roles, as a key modulator of this innate immune landscape. While full-length IL-33 accelerates GB progression by recruiting immunosuppressive myeloid cells, a nuclear-deficient variant lacking the nuclear localization sequence (ND-IL-33) potently halts tumor growth and prolongs survival. This growth-restrictive state is marked by the emergence of a distinct pro-inflammatory, anti-tumor myeloid population. Secretome profiling reveals that ND-IL-33-expressing glioma cells produce a unique repertoire of immune-stimulatory factors, consistent with enhanced innate immune activation, suggesting that loss of IL-33 nuclear activity reshapes tumor-intrinsic signaling to drive myeloid reprogramming. The clinical relevance of this biology is supported in patient-derived GB specimens, where high IL-33 expression is associated with increased immunosuppressive TAM infiltration and reduced overall survival. Ongoing bulk and single-cell RNA sequencing, integrated with functional co-culture assays, aims to define the transcriptional programs that distinguish tumor-inhibiting from tumor-promoting myeloid populations and to uncover therapeutic pathways capable of inducing this anti-tumor state. Together, these findings position IL-33 activity as a targetable regulator of myeloid plasticity in GB and offers a promising avenue to leverage innate immunity for improved therapeutic outcomes in glioblastoma. Citation Format: Tala-Maria Mouannes, Shyam V. Menon, Peipei Zeng, Jianbo Zhang, Isabelle Carrier, Eduardo Diez, Stephen M. Robbins, Donna L. Senger, . IL-33-mediated control of myeloid immunity in glioblastoma progression [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 7457.