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

Enteric glial cells (EGCs) have been recently recognized as key components of the colonic tumor microenvironment (TME) indicating their potential role in colorectal cancer (CRC) pathogenesis. Although EGCs modulate immune responses in other intestinal diseases, their interaction with the CRC immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in CRC murine models and patients, we found that EGCs acquire a reactive and immunomodulatory phenotype that drives tumor-associated macrophage (TAM) differentiation. Tumor-infiltrating monocytes direct CRC EGC phenotypic and functional switch via IL-1R signaling pathway. In turn, tumor EGCs promote monocyte differentiation towards pro-tumorigenic SPP1+ TAMs via secretion of IL-6. Finally, the distinct tumor EGC phenotype correlates with worse disease outcome in patients suffering from CRC. Our study reveals a previously unexplored and crucial neuroimmune interaction between EGCs and TAMs in the colorectal TME, providing important insights into CRC pathogenesis. ### Competing Interest Statement The authors have declared no competing interest.