Hypoxia-driven remodeling of SELENOP+ macrophages shapes T cell dynamics and promotes ovarian cancer metastasis

Abstract

High-grade serous ovarian cancer (HGSOC) is characterized by extensive transcoelomic dissemination and the accumulation of ascites. However, how site-specific tumor microenvironment (TME) drives progression remains unknown. Here we show the co-occurrence and spatial co-localization of SELENOP ⁺ macrophages and precursor exhausted CD8 ⁺ T cells and demonstrate that SELENOP ⁺ macrophages activate T cells via selenoprotein P in vitro and in vivo. We further identify a dynamic transition in the SELENOP ⁺ / SPP1 ⁺ macrophage populations as tumor metastasis, driven by increased hypoxia malignant epithelial cells through VEGFA-EPHB2 signaling. We also reveal that anti-VEGFA intervention controls ovarian tumor growth by increasing SELENOP ⁺ macrophages and cytotoxicity of CD8 ⁺ T cells in vivo. Taken together, these findings spotlight the role of tumor-induced TME remodeling in subverting immune-mediated tumor control and thus facilitating HGSOC metastasis in females. Collectively, our results provide a foundation for the development of targeted therapeutic interventions aimed at impeding HGSOC metastatic trajectory.