Macrophage-mediated brain-bone marrow crosstalk promotes chronic stress-induced glioma growth.

Abstract

Stress is associated with increased cancer morbidity and mortality. Here, we show that chronic stress accelerates glioma growth and reduces survival of tumor-bearing mice. Integrated multi-omics analysis of syngeneic glioma samples reveals stress-induced CD45⁺CD11b⁺C5aR1⁺ macrophages, termed stress-associated macrophages (SAMs). Using parabiosis experiments in mice, we demonstrate that SAMs are derived from bone marrow monocytes. Stress-activated sympathetic nerve promotes the differentiation of ADRB2⁺ bone marrow monocytes into SAMs, which can be antagonized by selective ablation of catecholaminergic nerves. Conditional knockout of C5ar1 in macrophages, or pharmacologic C5aR inhibition, reduces SAMs and attenuates stress-induced glioma tumor growth in vivo. SAMs exhibit elevated CD36 expression, leading to excessive intracellular lipid accumulation and peroxidization, dampening their phagocytotic capacity. SAMs abundance correlates with self-reported stress levels and portended prognosis in glioma patients. Collectively, these findings suggest that stress reprograms tumor immune microenvironment by inducing molecularly distinguished monocyte-derived macrophages, revealing potential opportunities for immune-based cancer therapies.