Senescence of tumor-specific Non-Classic Monocytes Facilitates Immune Suppression and Prostate Cancer Progression through Tumor and Host Immune Interactions

This study investigates the role of specific tumor-associated senescent non-classical monocytes (NC-Mo) in MYC amplification and PTEN deletion-mediated lethal prostate cancer progression, focusing on tumor-host immune interactions. Key genetic alterations, such as MYC amplification and PTEN deletion, lead to tumor cell apoptosis via mitochondrial Complex I dysfunction, driven by metabolic reprogramming characterized by increased glycolysis and arginine biosynthesis. A specific subtype of Ly6cLowCD43LowCXCR2+ NC-Mo is activated by the phagocytosis of apoptotic tumor cells and damage-associated molecular patterns (DAMPs) through TLR4 activation, promoting their differentiation into a senescent phenotype.TLR4 activation further induces NC-Mo to secrete TNF-α, which stimulates intra-tumor endothelial cells to produce G-CSF, circulating to the bone marrow and promoting the transition of classical monocytes into NC-Mo. Once senescent, NC-Mo secrete more TGF-β1, which enhances CXCL5 secretion from tumor cells, mainly via the AKT/PI3K pathway, creating a feedback loop that recruits more peripheral NC-Mo into the tumor microenvironment (TME). Additionally, IL-18 secreted by senescent NC-Mo suppresses T cells and NK cells, weakening both adaptive and innate immune responses in the TME. Targeting NC-Mo and key pathways, such as TLR4, CXCL5-CXCR2, and IL-18-IL18R, reduce immune suppression and inhibit tumor progression. These findings provide insights into how MYC/PTEN dysfunction accelerates prostate cancer progression through specific tumor-associated senescent NC-Mo, offering novel therapeutic opportunities.