Abstract
Immune checkpoint blockade (ICB) therapy has been extensively integrated into cancer clinical management. However, its overall response rate is limited due to the stagnating cancer-immunity cycle (CIC) caused by the immunosuppressive tumor microenvironment (TME). Here, a multi-pronged nanomedicine, defined as LCCS, was constructed by the self-assembly of lactate oxidase, catalase, chlorin e6, and sorafenib. Through cascade reactions, LCCS effectively reprogrammed the TME and re-initiated the CIC by depleting lactate, alleviating hypoxia, inducing immunogenic cell death, and normalizing tumor vessels. Immunological analyses indicated that treatment with LCCS decreased the infiltration of immunosuppressive cells while increasing the recruitment of immune effector cells in tumors. Leveraging the effective operation of the CIC, LCCS improved the efficacy of ICB therapy to inhibit breast cancer, and effectively induced the elimination of colorectal cancer and long-term immune memory. Therefore, multifunctional nanomedicines targeting CIC hold great potential for applications in cancer immunotherapy.