Iron-deficiency in the tumor microenvironment reprograms tumor-immune interactions in a sex biased manner

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Abstract Background Glioblastoma (GBM) is a sex-biased disease characterized by higher incidence and poorer survival in males. These sex differences are primarily driven by metabolic and immune signatures, with iron metabolism playing a major role. While iron is essential for tumor cell proliferation, it is also critical for T cell recruitment and function within the tumor microenvironment (TME). Clinical data indicates that iron deficiency impacts GBM survival in a sex-biased manner; however, the underlying mechanisms remain unexplored. Methods We employed a FTH1 heterozygous knockdown mouse model to induce tumor iron deficiency in GBM-bearing mice. TME dynamics were interrogated using flow cytometry and spatial transcriptomics (10X Xenium) to analyze immune infiltration, localization, and ligand-receptor signaling between GBM and immune cells. Results FTH1 knockdown resulted in iron deficiency in the GBM TME. Iron deficiency altered the TME dynamics in a sex biased manner. FTH1 knockdown in females caused an anti-inflammatory, cytokine deficient TME which failed to recruit CD4 and CD8 T cells. In males, FTH1 knockdown caused a proinflammatory environment by activating the innate immune response. Additionally, FTH1 knockdown increased the density of TAMs in the immediate surrounding of GBM cells in a sex biased manner. Conclusion These results demonstrate that tumor iron plays a sex-biased role in immune infiltration and anti-tumor immunity.

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