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Neuromedin U 'innervation' reprograms myeloid immunosuppression in neuroendocrine prostate cancer
Journal article   Peer reviewed

Neuromedin U 'innervation' reprograms myeloid immunosuppression in neuroendocrine prostate cancer

Michela Perego, Jozef Madzo, Andrew V Kossenkov, F Cansu Atilgan, Marcella Tazzari, Maria Maddalena Tumedei, Francesco Limarzi, Cristian Lolli, Giorgia Gurioli, Alessandro Fatatis, …
Oncogene, v 45(41), pp 4442-4453
01 Sep 2026
DOI: https://doi.org/10.1038/s41388-026-03969-5
PMID: 42675222

Abstract

Animals Calgranulin B - metabolism Carcinoma, Neuroendocrine - immunology Carcinoma, Neuroendocrine - pathology CD8-Positive T-Lymphocytes - immunology Cell Movement Humans Male Mice Mice, Transgenic Neuroendocrine Tumors - immunology Neuroendocrine Tumors - pathology Neuropeptides - genetics Neuropeptides - metabolism Neutrophils - immunology Neutrophils - metabolism Prostatic Neoplasms - genetics Prostatic Neoplasms - immunology Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology
Neuroendocrine prostate cancer (NEPC) is an increasingly recognized, highly aggressive disease variant with no actionable therapeutic targets and a life expectancy of 7 months or less. Using a transgenic mouse model, we now show that early stages of NEPC are associated with increased intraprostatic recruitment of Ly6G polymorphonuclear neutrophils (PMN) and reduced infiltration of CD8 T cells. This coincided with expansive transcriptional changes of increased cell viability and cell migration, as well as upregulation of multiple neuronal mediators with the neuropeptide, Neuromedin U (NMU) as the top hit (Z score = 4.34; FDR < 5%; p = 3.62 × 10 ). Analysis of a large cohort of human patient samples revealed that NMU was highly expressed in early and late stage prostate cancer, preferentially segregating with AR /NE metastases. Exposure of PMN to recombinant NMU was sufficient to stimulate cell migration, inflammatory gene expression with increased levels of the cytokine-like alarmin, S100A9 and suppression of T cell proliferation. Genetic or pharmacological targeting of NMU/S100A9 signaling inhibited NEPC growth, reinvigorated an intratumoral immune microenvironment via recruitment of tumor antigen-specific CD8 T cells with 'stem-like' (TCF1 /PD1 ) and cytotoxic (GrzB /KLRG1 ) properties and enhanced the activity of therapeutic immune checkpoint inhibition, in vivo. Therefore, NMU 'innervation' drives myeloid immunosuppression in NEPC and provides a therapeutic target to restore sensitivity to immunotherapy in this highly refractory malignancy.

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