Therapeutic Nanovaccines Reshape the Metabolic and Immune Microenvironment for Enhancing Immunotherapy of Primary and Lymphatic Metastatic Tumors

Abstract The effectiveness of anti‐metastasis therapy is hampered by the highly immunosuppressive microenvironment found in both tumor tissues and lymph nodes. In this work, a therapeutic nanovaccine, CaGlu NPs, is introduced composed of calcium carbonate nanoparticles (CaCO 3 NPs) and β‐glucan. Through the synergistic effect of CaCO 3 NPs and β‐glucan, CaGlu NPs can induce immunogenic cell death in tumor tissues, repolarize tumor macrophages, reverse the immunosuppressive tumor microenvironment, effectively activate antigen‐specific cytotoxic T lymphocytes, promote dendritic cells maturation, and eventually elicit an effective anti‐tumor immune response in both primary tumors and metastatic lymph nodes. Meanwhile, CaGlu NPs can remodel the metabolic microenvironment in tumors and lymph nodes by decreasing the expression of lactate dehydrogenase A and hypoxia‐inducible factor‐1α, further enhancing the anti‐tumor immune response. CaGlu NPs also inhibit tumor angiogenesis and lymphangiogenesis and induce long‐term immune memory effects. This therapeutic nanovaccine strategy, which simultaneously remodels the metabolic and immunosuppressive microenvironments in tumors and metastatic lymph nodes, showed strong anti‐metastatic effects in vivo. This study presents a promising approach to effectively treat lymph node metastatic tumors using nanomaterial‐assisted immunotherapies and underscores its broad potential for clinical applications.