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Cancer-associated fibroblast-derived CCL5 promotes cisplatin resistance in neuroendocrine prostate cancer

ABSTRACT: Chemoresistance remains a significant challenge in the treatment of neuroendocrine prostate cancer (NEPC), a highly aggressive and lethal subtype of prostate cancer. Here, we identify a tumor-stromal interaction mediated by the CCL5/CCR5 signaling axis that drives cisplatin resistance. Cisplatin-induced DNA damage promotes a cGAS-STING–dependent senescence program in cancer-associated fibroblasts (CAFs), resulting in the secretion of CCL5, a key senescence-associated secretory phenotype factor. CAF-derived CCL5 binds to CCR5 on tumor cells, promoting the formation of a CCR5/β-arrestin1/p85 complex that activates the PI3K/AKT signaling pathway. This activation enhances DNA repair, protecting tumor cells from cisplatin-induced apoptosis. Pharmacologic inhibition of the CCL5/CCR5 pathway using maraviroc, an FDA-approved CCR5 antagonist, sensitizes NEPC cells to cisplatin treatment and significantly prolongs survival in an NEPC mouse model. These findings establish the CCL5/CCR5 axis as a critical mediator of tumor-stromal crosstalk and provide a promising therapeutic strategy for overcoming chemoresistance in NEPC.

ORGANISM(S): Mus musculus

PROVIDER: GSE287963 | GEO | 2025/12/03

REPOSITORIES: GEO

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Project description:Senescent foamy macrophages are the key pathogenic drivers of atherosclerosis (AS) progression and plaque stability. The RNA N6-methyladenosine (m6A) modification plays an important role in the development of various diseases. However, its role in foamy macrophage aging during AS is still not clarified. To assess m6A methylation levels and m6A modifying enzyme profiles, the infiltrated macrophages were sorted using CD68+ magnetic beads from plaque tissues of patients with AS and high-fat diet feeding Apoe-/- mice. The ALKBH5f/f, Lyz2Cre, Apoe-/- mice were constructed to observe senescent macrophage infiltrated in plaques and AS progression. The RNA-seq, MeRIP, RIP and dual luciferase assays were performed to explore the mechanisms of ALKBH5-mediated formation of senescent macrophage. Downregulated m6A methylation levels and upregulated ALKBH5 expression were observed in aortic plaques and infiltrated macrophages from AS patients and mice. Compared with control mice, ALKBH5f/f, Lyz2Cre, Apoe-/- mice decreased AS plaques and enhanced plaque stability by suppressing senescence of foamy macrophages and senescence-associated secretory phenotypes. In addition, the data of the RNA-seq, MeRIP, RIP and dual luciferase assays showed that ALKBH5 deletion reduced the mRNA level of CC chemokine ligand 5 (CCL5) by increased m6A methylation in macrophages. Actinomycin D assay indicated ALBH5 knockout destroyed stability of Ccl5 mRNA. Mechanismly, ALKBH5 promotes senescent macrophage formation by CCL5/CC chemokine receptor 5 (CCR5)/mTORC1/autophagy signaling. And ALKBH5 induced macrophage derived CCL5 recruits increasingly CD8+IFNγ+ T cells by CCL5-CCR5 axis. Furthermore, the application of ALKBH5 inhibitor IOX-1 and CCR5 monoclonal antibody Adaptavir are potential clinical interventions for the inhibition of senescent macrophage formation and AS progress. Myeloid ALKBH5 deletion mitigates AS progression by suppressing the formation of senescent macrophages and the recruitment of CD8+IFNγ+ T cells. These findings favour the ALKBH5/CCL5/CCR5 signaling as novel targets for atherosclerosis therapy.

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Cancer-associated fibroblast-derived CCL5 promotes cisplatin resistance in neuroendocrine prostate cancer

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