Despite the remarkable success and efficacy of
immune checkpoint blockade (ICB)
therapy such as anti-PD-L1 antibody in treating
cancers, myeloid-derived suppressor cells (MDSCs) that lead to the formation of the protumor immunosuppressive microenvironment are one of the major contributors to ICB resistance. Therefore, inhibition of MDSC accumulation and function is critical for further enhancing the therapeutic efficacy of anti-PD-L1 antibody in a majority of
cancer patients.
Artemisinin (ART), the most effective
antimalarial drug with tumoricidal and immunoregulatory activities, is a potential option for
cancer treatment. Although ART is reported to reduce MDSC levels in 4T1
breast tumor model and improve the therapeutic efficacy of anti-PD-L1 antibody in
T cell lymphoma-bearing mice, how ART influences MDSC accumulation, function, and molecular pathways as well as MDSC-mediated anti-PD-L1 resistance in
melanoma or liver
tumors remains unknown. Here, we reported that ART blocks the accumulation and function of MDSCs by polarizing M2-like
tumor-promoting phenotype towards M1-like antitumor one. This switch is regulated via PI3K/AKT, mTOR, and MAPK signaling pathways. Targeting MDSCs by ART could significantly reduce
tumor growth in various mouse models. More importantly, the
ART therapy remarkably enhanced the efficacy of anti-PD-L1
immunotherapy in
tumor-bearing mice through promoting antitumor T cell infiltration and proliferation. These findings indicate that ART controls the functional polarization of MDSCs and targeting MDSCs by ART provides a novel therapeutic strategy to enhance anti-PD-L1
cancer immunotherapy.