Nature Communications (Sep 2024)

IL36G-producing neutrophil-like monocytes promote cachexia in cancer

  • Yoshihiro Hayashi,
  • Yasushige Kamimura-Aoyagi,
  • Sayuri Nishikawa,
  • Rena Noka,
  • Rika Iwata,
  • Asami Iwabuchi,
  • Yushin Watanabe,
  • Natsumi Matsunuma,
  • Kanako Yuki,
  • Hiroki Kobayashi,
  • Yuka Harada,
  • Hironori Harada

DOI
https://doi.org/10.1038/s41467-024-51873-x
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 14

Abstract

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Abstract Most patients with advanced cancer develop cachexia, a multifactorial syndrome characterized by progressive skeletal muscle wasting. Despite its catastrophic impact on survival, the critical mediators responsible for cancer cachexia development remain poorly defined. Here, we show that a distinct subset of neutrophil-like monocytes, which we term cachexia-inducible monocytes (CiMs), emerges in the advanced cancer milieu and promotes skeletal muscle loss. Unbiased transcriptome analysis reveals that interleukin 36 gamma (IL36G)-producing CD38+ CiMs are induced in chronic monocytic blood cancer characterized by prominent cachexia. Notably, the emergence of CiMs and the activation of CiM-related gene signatures in monocytes are confirmed in various advanced solid cancers. Stimuli of toll-like receptor 4 signaling are responsible for the induction of CiMs. Genetic inhibition of IL36G-mediated signaling attenuates skeletal muscle loss and rescues cachexia phenotypes in advanced cancer models. These findings indicate that the IL36G-producing subset of neutrophil-like monocytes could be a potential therapeutic target in cancer cachexia.