Immunotherapy is an ascendant approach in cancer treatment.It shows more pronounced effects on killing cancer cells in a specific manner in particular against metastasis more than traditional techniques,such as chemotherapy or surgery.However,tumor immunosuppression limits the response of the immune system to cancer development.In this study,we developed a lipid-based nanocarrier doubly loaded with imiquimod(R837),a toll-like receptor 7 agonist,and caffeine,an adenosine receptor antagonist.This R837/caffeine loaded nanocarrier served as a nano-immunomodulator (RC-nIM) for combination treatment with radiotherapy (RT)against orthotopic breast cancer.RT-induced immunogenic cell death facilitated the production of tumor antigen and elicited the immune response in corporation with R837-medaited activation of antigen-presenting cells(APCs) while RC-nIMs being adopted.Additionally,caffeine,an adenosine analog,can successfully compete with adenosine in the tumor.The tumor-bearing mice that received RT together with RC-nIMs experienced the best antitumor effects and exhibited higher levels of T cells and APCs within the tumor;the growth of secondary tumors was also limited.This work serves as a proof-of-concept study for the development of a new im-munotherapy strategy against cancer.