Peritoneal resident macrophages constitute an immunosuppressive environment in peritoneal metastasized colorectal cancer

J. Saris, A. Y. F. Li Yim, S. Bootsma, K. J. Lenos, R. Franco Fernandez, H. N. Khan, J. Verhoeff, D. Poel, N. M. Mrzlikar, L. Xiong, M. P. Schijven, N. C. T. Grieken, O. Kranenburg, M. E. Wildenberg, A. Logiantara, C. Jongerius, J. J. Garcia Vallejo, S. S. Gisbertz, S. Derks, J. B. Tuynman, G. R. A. M. D’Haens, L. Vermeulen and J. Grootjans ()
Additional contact information
J. Saris: University of Amsterdam
A. Y. F. Li Yim: University of Amsterdam
S. Bootsma: Amsterdam Gastroenterology Endocrinology Metabolism
K. J. Lenos: Amsterdam Gastroenterology Endocrinology Metabolism
R. Franco Fernandez: Amsterdam Gastroenterology Endocrinology Metabolism
H. N. Khan: Amsterdam Gastroenterology Endocrinology Metabolism
J. Verhoeff: Amsterdam Gastroenterology Endocrinology Metabolism
D. Poel: Amsterdam Gastroenterology Endocrinology Metabolism
N. M. Mrzlikar: Amsterdam Gastroenterology Endocrinology Metabolism
L. Xiong: University of Amsterdam
M. P. Schijven: Amsterdam Gastroenterology Endocrinology Metabolism
N. C. T. Grieken: Cancer Center Amsterdam
O. Kranenburg: University Medical Center Utrecht
M. E. Wildenberg: University of Amsterdam
A. Logiantara: University of Amsterdam
C. Jongerius: Amsterdam Gastroenterology Endocrinology Metabolism
J. J. Garcia Vallejo: Cancer Center Amsterdam
S. S. Gisbertz: Cancer Center Amsterdam
S. Derks: Cancer Center Amsterdam
J. B. Tuynman: Cancer Center Amsterdam
G. R. A. M. D’Haens: University of Amsterdam
L. Vermeulen: Amsterdam Gastroenterology Endocrinology Metabolism
J. Grootjans: University of Amsterdam

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Patients with peritoneal metastasized colorectal cancer (PM-CRC) have a dismal prognosis. We hypothesized that an immunosuppressive environment in the peritoneal cavity underlies poor prognosis. We define the composition of the human peritoneal immune system (PerIS) using single-cell technologies in 18 patients with- and without PM-CRC, as well as in matched peritoneal metastases (n = 8). Here we show that the PerIS contains abundant immunosuppressive C1Q+VSIG4+ and SPP1+VSIG4+ peritoneal-resident macrophages (PRMs), as well as monocyte-like cavity macrophages (mono-CMs), which share features with tumor-associated macrophages, even in homeostasis. In PM-CRC, expression of immunosuppressive cytokines IL10 and VEGF increases, while simultaneously expression of antigen-presenting molecules decreases in PRMs. These intratumoral suppressive PRMs originate from the PerIS, and intraperitoneal depletion of PRMs in vivo using anti-CSF1R combined with anti-PD1 significantly reduces tumor burden and improves survival. Thus, PRMs define a metastatic site-specific immunosuppressive niche, and targeting PRMs is a promising treatment strategy for PM-CRC.

Date: 2025
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DOI: 10.1038/s41467-025-58999-6

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