Metastatic triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Combination of systemic chemotherapy and immune checkpoint blockade is effective but of limited benefit due to insufficient in...Metastatic triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Combination of systemic chemotherapy and immune checkpoint blockade is effective but of limited benefit due to insufficient intratumoral infiltration of cytotoxic T lymphocytes(CTLs)and the accumulation of immunosuppressive cells.Herein,we designed a lenvatinib-and vadimezan-loaded synthetic high-density lipoprotein(LV-sHDL)for combinational immunochemotherapy of metastatic TNBC.The LV-sHDL targeted scavenger receptor class B type 1-overexpressing 4T1 cells in the tumor after intravenous injection.The multitargeted tyrosine kinase inhibitor(TKI)lenvatinib induced immunogenic cell death of the cancer cells,and the stimulator of interferon genes(STING)agonist vadimezan triggered local inflammation to facilitate dendritic cell maturation and antitumor macrophage differentiation,which synergistically improved the intratumoral infiltration of total and active CTLs by 33-and 13-fold,respectively.LV-sHDL inhibited the growth of orthotopic 4T1 tumors,reduced pulmonary metastasis,and prolonged the survival of animals.The efficacy could be further improved when LV-sHDL was used in combination with antibody against programmed cell death ligand 1.This study highlights the combination use of multitargeted TKI and STING agonist a promising treatment for metastatic TNBC.展开更多
基金the National Natural Science Foundation of China (32171374, 31870995 and 81671808)the Shandong Provincial Natural Science Foundation (ZR2019ZD25, China) for financial support
文摘Metastatic triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Combination of systemic chemotherapy and immune checkpoint blockade is effective but of limited benefit due to insufficient intratumoral infiltration of cytotoxic T lymphocytes(CTLs)and the accumulation of immunosuppressive cells.Herein,we designed a lenvatinib-and vadimezan-loaded synthetic high-density lipoprotein(LV-sHDL)for combinational immunochemotherapy of metastatic TNBC.The LV-sHDL targeted scavenger receptor class B type 1-overexpressing 4T1 cells in the tumor after intravenous injection.The multitargeted tyrosine kinase inhibitor(TKI)lenvatinib induced immunogenic cell death of the cancer cells,and the stimulator of interferon genes(STING)agonist vadimezan triggered local inflammation to facilitate dendritic cell maturation and antitumor macrophage differentiation,which synergistically improved the intratumoral infiltration of total and active CTLs by 33-and 13-fold,respectively.LV-sHDL inhibited the growth of orthotopic 4T1 tumors,reduced pulmonary metastasis,and prolonged the survival of animals.The efficacy could be further improved when LV-sHDL was used in combination with antibody against programmed cell death ligand 1.This study highlights the combination use of multitargeted TKI and STING agonist a promising treatment for metastatic TNBC.
