Abstract
Tumor-associated macrophages (TAMs) frequently help to sustain tumor growth and mediate immune suppression in the tumor microenvironment (TME). Here, we identified a subset of iron-loaded, pro-inflammatory TAMs localized in hemorrhagic areas of the TME. The occurrence of iron-loaded TAMs (iTAMs) correlated with reduced tumor size in patients with non-small cell lung cancer. Ex vivo experiments established that TAMs exposed to hemolytic red blood cells (RBCs) were converted into pro-inflammatory macrophages capable of directly killing tumor cells. This anti-tumor effect could also be elicited via iron oxide nanoparticles. When tested in vivo, tumors injected with such iron oxide nanoparticles led to significantly smaller tumor sizes compared to controls. These results identify hemolytic RBCs and iron as novel players in the TME that repolarize TAMs to exert direct anti-tumor effector function. Thus, the delivery of iron to TAMs emerges as a simple adjuvant therapeutic strategy to promote anti-cancer immune responses.
Highlights
The tumor microenvironment (TME) significantly influences tumor progression [1]
To explore whether iron-loaded tumor-associated macrophages (TAMs) are associated with specific areas in the tumor, we performed iron staining in Tissue microarrays (TMAs) from 116 patients with non-small cell lung cancer (NSCLC)
Our results show that the responses of macrophages to red blood cells (RBCs) in the in vitro model mirrored those in the hemorrhagic areas of the TME, with iron accumulation in macrophages and a shift toward a pro-inflammatory phenotype
Summary
The tumor microenvironment (TME) significantly influences tumor progression [1]. It is characterized by high cellular complexity, including fibroblasts, stroma, and blood vessels, and infiltrates of immune cells. Tumor-associated macrophages (TAMs) are a major immune component of the TME [2,3,4]. Macrophages display a high degree of functional plasticity, reflected by their capacity to integrate diverse signals from the microenvironment and to acquire distinct phenotypes [6,7,8,9,10,11]. In the TME, pro-inflammatory “M1 macrophages” counteract tumor growth either by activating adaptive immune responses or by directly killing tumor cells [12,13,14,15].
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