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(3)) 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(3)).