Tumors and Their Microenvironment Dual-Targeting Chemotherapy with Local Immune Adjuvant Therapy for Effective Antitumor Immunity against Breast Cancer.

Chemotherapy turns tumor cells into "tumor vaccines" by immunogenic cell death (ICD). However, it remains a challenge to exploit chemotherapy-induced "tumor vaccines" for solid cancer immunotherapy due to the inefficient effector T cells activation and tumor microenvironment immunosuppression. Here, a matrix metalloprotease 2 responsive liposome (PEG-FA-Lip) composed of cleavable PEG chains covering the folate (FA)-modified liposome is developed to deliver ICD inducer doxorubicin. In breast cancer-bearing mice, PEG-FA-Lip targets both 4T1 breast cancer cells and M2-tumor associated macrophages (M2-TAMs) via FA-receptor mediated endocytosis, resulting in abundant "tumor vaccines" and efficient elimination of M2-TAMs. The combination of local cytosine-phosphate-guanine (CpG) therapy facilitates PEG-FA-Lip induced "tumor vaccines" to effectively arouse systematic effector T cells immune response through promoting dendritic cell maturation and immunostimulatory cytokines secretion. The simultaneous elimination of M2-TAMs ensures the activated effector T cells exert antitumor immunity within tumor via decreasing immunosuppressive cytokines secretion and tumor infiltration of Treg cells. After receiving the combined treatment, 30.1% of breast cancer-bearing mice (initial tumor volume > 100 mm) achieves the goal of tumor eradication. Remarkably, this combination therapy greatly inhibits lung metastasis and controls the growth of already metastasized breast cancers (initial tumor volume > 100 mm).