IL-28B reprograms tumor-associated macrophages to promote anti-tumor effects in colon cancer

The type III interferon family (IFN-III), including IFN-λ3 [interleukin (IL)-28B], has antiviral, anti-tumor, and immunomodulatory activities. Although the IL-28B anti-tumor effect has been extensively explored, its underlying mechanism remains unclear. Here, we explored IL-28B effects on colon cancer. Our results show that IL-28B significantly inhibits colon cancer progression in a mouse MC38 tumor cell colonization model and colitis-associated colorectal tumor model. Interestingly, IL-28B does not directly promote apoptosis or inhibit MC38 tumor cell proliferation in vitro. Rather, IL-28B treatment has indirect anti-tumor activity by downregulating tumor-associated macrophages. Furthermore, IL-28B inhibits M2 macrophage polarization in vitro, while also halting M2 macrophage differentiation predominantly via inhibition of the signal transducer and activator of transcription (STAT)3 and c-Jun N-terminal kinase (JNK) signaling pathways. Our findings revealed that IL-28B inhibits M2 macrophages in the tumor microenvironment to delay colon cancer progression. These findings provide novel evidence of IL-28B anti-tumor and immunomodulatory activities.