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Tumor-Associated Senescent Non-Classical Monocytes Promote Immune Suppression and Progression of Advanced Prostate Cancer [CUT&Run]

ABSTRACT: Prostate cancer, a leading cause of male cancer mortality, poses major therapeutic hurdles due to its immunosuppressive tumor microenvironment (TME). We link MYC amplification and PTEN deletion to metastatic prostate adenocarcinoma and identify a specific population of tumor-associated non-classical monocytes (staNC-Mo, CD11b+Ly6cLowCD14HiCD43LowCX3CR1Low) as key mediators of immune suppression. MYC overexpression with Pten loss induces mitochondrial stress, triggering tumor-cell apoptosis and HSP60 release. The HSP60/TLR4 signaling activates staNC-Mo to secrete TNF-α, stimulating endothelial G-CSF production and driving staNC-Mo differentiation in bone marrow and spleen. CD14-dependent phagocytosis of apoptotic tumor cells drives staNC-Mo senescence and TGF-β1 secretion. TGF-β1 activates PI3K/AKT signaling in tumor cells, inducing CXCL5 secretion and reinforcing staNC-Mo recrutiment. Senescent staNC-Mo also release IL-18, suppressing innate and adaptive immunity. Targeting Ly6c, CD14, CXCL5-CXCR2, TLR4, or IL-18 reduces staNC-Mo accumulation, relieves TME immunosuppression, and inhibits tumor progression, suggesting therapeutic strategies for advanced prostate cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE345439 | GEO | 2026/09/02

REPOSITORIES: GEO

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Project description:Prostate cancer remains a leading cause of cancer-related mortality in men, with metastatic cases presenting significant therapeutic challenges due to genetic alterations that drive disease progression and immune evasion. While localized prostate cancer generally has favorable outcomes, metastatic disease is associated with much poorer survival rates. 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.

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Tumor-Associated Senescent Non-Classical Monocytes Promote Immune Suppression and Progression of Advanced Prostate Cancer [CUT&Run]

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