Background IL-37 has been shown to inhibit tumor growth in various cancer types. However, the immune regulatory function of IL-37 in the tumor microenvironment is unclear. Recent studies have suggested that IL-37 could recruit natural killer cells and promote dendritic cell or macrophage functions to inhibit tumor development using subcutaneous or xenograft mouse models, which may not reflect the organ-specific tumor microenvironment.

Methods We established a humanized patient-derived xenograft (PDX) hepatocellular carcinoma (HCC) model and three murine orthotopic HCC models to study the function of IL-37 in the tumor microenvironment.

Results We found that IL-37 inhibited HCC growth and promoted T cell activation. Further study revealed that IL-37 impaired the immune-suppressive capacity of myeloid derived suppressor cells (MDSCs). Pretreatment of MDSCs with IL-37 before adoptive transfer attenuated their tumor-promoting function in HCC tumor-bearing mice. Moreover, IL-37 promoted both glycolysis and OXPHOS in MDSCs, resulting in the upregulation of ATP release, which impaired the immune-suppressive capacity of MDSCs.

Conclusions Taken together, we demonstrated that IL-37 inhibited tumor development through dampening MDSC’s immune-suppressive capacity in the tumor microenvironment via metabolic reprogramming, making it a promising target for future cancer immunotherapy.