Senescent macrophages: A new "old" player in lung cancer development

Abstract

Senescent cells accumulate following oncogene induction, but their role in transformation remains unclear. Prieto et al. and Haston et al. found that senescent cells in premalignant lung lesions are mainly macrophages that promote lung tumorigenesis, and removing them through senolytic approaches can prevent malignant progression.

Figure 1.. Senescent macrophages that accrue following oncogene-induced senescence promote lung tumorigenesis, and their clearance delays tumor progression.

In premalignant hyperplastic and adenoma lesions in the lungs of mouse models and patient samples, Prieto et al. observe the accumulation of senescent CXCR1⁺ alveolar macrophages, and Haston et al. senescent FOLR2⁺/CD163⁺ interstitial macrophages and PECAM⁺ endothelial cells. Depletion of these senescent cells via pharmacogenetic p16 ablation, senolytic compounds, or macrophage depleting agents delays tumor onset and progression, and remodels the immune suppressive lung TME to activate cytotoxic CD8⁺ T cells. These findings suggests that senolytic therapy that targets senescent macrophage populations may be a novel approach to intercept lung cancer. Figure created with Biorender.com.