IL-1R signaling drives enteric glia-macrophage interaction in colorectal cancer progression

ABSTRACT Enteric glial cells (EGCs) have been implicated in colorectal cancer (CRC) pathogenesis. However, their precise mechanisms of interaction with the CRC immune cell compartment and pro-tumorigenic role remain unclear. This study aimed to investigate the immunomodulatory effects of EGCs on tumor-associated macrophages (TAMs) and their involvement in CRC progression. Using EGC depletion and supplementation models, we assessed the impact of EGCs on the immunomodulation of orthotopic murine CRC. Furthermore, by making use of Bulk RNA-sequencing of CRC EGCs and single-cell sequencing of the tumor microenvironment, we identified the factors involved in the EGC-TAM crosstalk. Findings demonstrate that EGCs acquire a reactive and immunomodulatory phenotype in both murine CRC models and patients, influencing TAM differentiation. Mechanistically, secretion of IL-1 by tumor-infiltrating monocytes and macrophages triggers the phenotypic and functional switch of CRC EGCs via IL-1R. Consequently, tumor EGCs secrete IL-6, promoting the differentiation of monocytes into pro-tumorigenic SPP1 + TAMs. Importantly, the reactive tumor EGCs phenotype correlates with worse disease outcomes in preclinical models and CRC patients. Here we uncover a previously unexplored neuroimmune interaction between EGCs and TAMs within the colorectal tumor microenvironment, informing potential therapeutic strategies and enhancing our understanding of CRC progression. eTOC Summary Our study unveils a novel neuroimmune interaction between enteric glia and TAMs in colon carcinoma. Monocyte/Macrophage-derived IL-1 activates enteric glia, leading to the differentiation of pro-tumorigenic SPP1 + TAMs via glial-derived IL-6. Blocking glial IL-1R-signaling reduces colonic tumor lesions, highlighting IL-1R as a potential therapeutic target.