IL-1b derived from mix-polarized macrophages activates fibroblasts and synergistically form cancer promoting microenvironment

Patients with diffuse-type gastric cancer (DGC) had a poor prognosis. However, the complicated mechanism underlying the interaction between DGC cells and the tumor microenvironment (TME) remains unknown. An original 3D triple coculture system was used to examine the multicellular crosstalk among DGC cells, fibroblasts, and macrophages. We notably identified M1/M2 hybrid macrophages secreting IL-1b, which induced the conversion of noncancerous fibroblasts (NFs) into cancer-associated fibroblast-like (CAF-like) cells. On the other hand, IL-6 and colony stimulating factor 2 (GM-CSF) in the TME cooperated to maintain the steady state of M1/M2 hybrid macrophages. Our research revealed a positive feedback loop in the TME, which is helpful for comprehensively understanding the polarization of macrophages in the TME and conducive to the improvement of DGC treatment methods.