Fibrinogen-like 2 in tumor-associated macrophage-derived extracellular vesicles shapes an immunosuppressive microenvironment in colorectal liver metastases by promoting tumor stemness and neutrophil extracellular traps formation

Investigating the mechanisms underlying the development of an immunosuppressive microenvironment within colorectal liver metastases (CRLM) is important for identifying synergistic targets for immunotherapy. The regulatory role of tumor-associated macrophage-derived extracellular vesicles (TAM-EVs) in the immune microenvironment of CRLM has not yet been fully explored. Here, we found that TAM-EVs shaped the immunosuppressive microenvironment at the invasive front in murine CRLM models, thus dampening anti-PD-1 immunotherapy. This environment is characterized by an increased tumor stemness potential and abundant neutrophil extracellular traps (NETs) formation. Mechanistically, TAM-EVs-derived fibrinogen-like 2 (FGL2) interacts with the FCGR2B receptor in tumor cells, which further activates a p-STAT3/IL-1(3 positive feedback loop to increase the stemness potential of cancer cells, whereas IL-1(3 mediates the communication between cancer cells and neutrophils. The use of an anti-IL-1(3 monoclonal antibody can reduce NETs production and synergize with anti-PD-1 immunotherapy, which offers clinical translational significance for CRLM therapy. The FGL2/p-STAT3/IL-1(3 loop correlates with an immunosuppressive microenvironment and poor prognosis in human patients with CRLM. Our results revealed the potential of enhancing the efficacy of immunotherapy via the targeted clearance of NETs using anti-IL-1(3 monoclonal antibodies, which have significant clinical translational value in the treatment of CRLM.