Low-dose metronomic gemcitabine pretreatments overcome the resistance of breast cancer to immune checkpoint therapy.

Immunotherapy has revolutionized cancer management. However, response to immunotherapy is heterogeneous. Thus, strategies to improve antitumor immune responses in resistant tumors, such as breast cancer, are urgently needed. Established murine tumors were treated with anti-CTLA4 or anti-PD-1 alone or combined with metronomic gemcitabine (met-GEM). Tumor vascular function, immune cell tumor infiltration and gene transcription were determined. Low-dose met-GEM (2 mg/kg) treatments improved tumor vessel perfusion and increased tumor-infiltrating T cells. Notably, low-dose met-GEM pretreatments converted resistant tumors to respond to immunotherapy. Moreover, combined therapy reduced tumor vessel density, improved tumor vessel perfusion, increased T-cell tumor infiltration and upregulated the expression of some anticancer genes. Low-dose met-GEM pretreatment reconditioned the tumor immune microenvironment and improved immunotherapy efficacy in murine breast cancer.