IL36G-producing neutrophil-like monocytes promote cachexia in cancer

Sep 21, 2026

Uploaded by Theodore

Advanced cancer frequently causes cachexia, a multifactorial syndrome marked by progressive skeletal muscle wasting and poor survival outcomes. Mediators driving cancer-cachexia development remain insufficiently defined. This article identifies a neutrophil-like monocyte subset termed cachexia-inducible monocytes (CiMs) that emerges in advanced cancer and promotes muscle loss. Unbiased transcriptome analysis shows that IL36G-producing CD38+ CiMs are induced in chronic monocytic blood cancer with marked cachexia, and similar CiM gene signatures occur across advanced solid tumors. Toll-like receptor 4 signaling induces CiMs, while IL36G signaling inhibition attenuates muscle loss and rescues cachexia phenotypes in advanced cancer models, suggesting IL36G-producing CiMs as potential therapeutic targets.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Background

Cachexia and unmet therapeutic needs

Immune cells and myeloid reprogramming in cancer

Clinical links between monocytes, neutrophils, and cachexia

Results

Cachexia development in monocytic leukemia mice

Article [https://doi.org/10.1038/s41467-024-51873-x](https://doi.org/10.1038/s41467-024-51873-x) IL36G-producing neutrophil-like monocytes promote cachexia in cancer Received: 24 September 2023 | Accepted: 19 August 2024 | | --- | | | | Check for updates | Yoshihiro Hayashi 1,2,4 , Yasushige Kamimura-Aoyagi1,4, Sayuri Nishikawa1, Rena Noka1, Rika Iwata1, Asami Iwabuchi1, Yushin Watanabe1, Natsumi Matsunuma1, Kanako Yuki1, Hiroki Kobayashi 1, Yuka Harada 3 & Hironori Harada 1 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. Cachexia comprises a group of multifactorial inﬂammatory and metabolic syndromes deﬁned by progressive weight loss and skeletal muscle wasting independent ofwhether fat mass loss occurs1,2. Cancerassociated cachexia is often observed in patients with various cancers, particularly in advanced stages, with a prevalence of approximately 80%1. However, the mechanisms underlying cachexia development in cancer pathogenesis remain unclear. Although cachexia is estimated to account for up to 30% of all cancer-related deaths3, limited therapeutic options are currently available. Recent advances in cancer biology have uncovered critical proand anti-tumor roles of immune cells in the generation and progression of cancer pathogenesis4–6. Among these immune cells, myeloid innate immune cells, including neutrophils, monocytes, macrophages, and dendritic cells, are key components of the complex cancer- associated ecosystem7–15. Accumulating evidence demonstrates that cancer cells can reprogram these immune cells toward a tumorpromoting phenotype, not only within the tumor microenvironment (TME) but also in systemic circulation. This can facilitate tumor growth, invasion, metastasis, immune escape, and therapy resistance, leading to disease progression and dismal outcomes in patients with cancer14,16. Given that cachexia primarily occurs in advanced cancer1, tumor-educated myeloid innate immune cells likely contribute to the pathogenesis of cancer cachexia. Indeed, increased expression of several cytokines and chemokines, such as tumor necrosis factor (TNF), interleukin 1 (IL1), and IL6, has been reported in patients with cancer cachexia17. Besides tumor cells, many myeloid innate immune cells are capable of producing these proinﬂammatory factors18. C-C motif chemokine ligand (CCL2), a master chemoattractant for 1Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. 2Laboratory of Cancer Pathobiology and Therapeutics, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan. 3Clinical Research Support Center, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan. 4These authors contributed equally: Yoshihiro Hayashi, Yasushige Kamimura-Aoyagi. e-mail: [yshrhys@fc.ritsumei.ac.jp](yshrhys@fc.ritsumei.ac.jp); [hharada@toya

FAQs

What role do cachexia-inducible monocytes (CiMs) play in advanced cancer?

CiMs emerge in the advanced cancer setting and promote skeletal muscle loss, contributing to cachexia development.

How are CiMs induced in these cancer contexts?

Toll-like receptor 4 signaling drives the induction of CiMs, including IL36G-producing CD38+ subsets.

Does blocking IL36G signaling affect cachexia outcomes?

Genetic inhibition of IL36G-mediated signaling reduces skeletal muscle loss and rescues cachexia phenotypes in advanced cancer models.

Sep 21, 2026

Uploaded by Theodore