CD169+ Macrophage‐Targeted Immunomodulator to Restore Phagocytic Function and Enhance Antigen Presentation for Lymphatic Metastasis Eradication

A CD169+ macrophage‐targeted immunomodulator (G‐LNP@S‐D) is developed to co‐deliver a SHP2 inhibitor and STING agonist, thereby restoring phagocytic function, enhancing antigen presentation by CD169+ macrophages, and promoting T cell priming to eradicate lymphatic metastasis. Abstract Lymphatic metastasis is a major cause of tumor treatment failure, with the immunosuppressive status of lymphatic macrophages significantly impairing antitumor immunity. In this study, it is found that CD169+ macrophages in lymphatic metastasis exhibit impaired phagocytic activity and diminished antigen‐presenting capacity, which correlates with suppressed antitumor immune responses. Based on these discoveries, a CD169+ macrophage‐targeted immunomodulator (designated as G‐LNP@S‐D) is fabricated to restore phagocytic function and enhance antigen presentation for lymphatic metastasis eradication. G‐LNP@S‐D consists of GM1‐functionalized liposomes co‐encapsulating the SHP2 inhibitor SHP099 and the STING agonist DMXAA, enabling sequential lymph node‐ and CD169+ macrophage‐specific drug delivery. Mechanistically, G‐LNP@S‐D not only restores the phagocytic capacity of CD169+ macrophages to eliminate tumor cells but also activates the STING pathway to enhance antigen presentation and subsequent T cell priming. Immunological profiling confirms that G‐LNP@S‐D treatment promotes the infiltration of CD4+ and CD8+ T cells in both TDLNs and primary tumors. Importantly, G‐LNP@S‐D exerts systemic immunomodulatory effects for directly eradicating lymphatic metastases. This study elucidates a sophisticated lymph node immune‐modulation strategy and provides a promising therapeutic approach to treat lymphatic metastasis. A CD169 + macrophage-targeted immunomodulator (G-LNP@S-D) is developed to co-deliver a SHP2 inhibitor and STING agonist, thereby restoring phagocytic function, enhancing antigen presentation by CD169 + macrophages, and promoting T cell priming to eradicate lymphatic metastasis. Abstract Lymphatic metastasis is a major cause of tumor treatment failure, with the immunosuppressive status of lymphatic macrophages significantly impairing antitumor immunity. In this study, it is found that CD169 + macrophages in lymphatic metastasis exhibit impaired phagocytic activity and diminished antigen-presenting capacity, which correlates with suppressed antitumor immune responses. Based on these discoveries, a CD169 + macrophage-targeted immunomodulator (designated as G-LNP@S-D) is fabricated to restore phagocytic function and enhance antigen presentation for lymphatic metastasis eradication. G-LNP@S-D consists of GM1-functionalized liposomes co-encapsulating the SHP2 inhibitor SHP099 and the STING agonist DMXAA, enabling sequential lymph node- and CD169 + macrophage-specific drug delivery. Mechanistically, G-LNP@S-D not only restores the phagocytic capacity of CD169 + macrophages to eliminate tumor cells but also activates the STING pathway to enhance antigen presentation and subsequent T cell priming. Immunological profiling confirms that G-LNP@S-D treatment promotes the infiltration of CD4 + and CD8 + T cells in both TDLNs and primary tumors. Importantly, G-LNP@S-D exerts systemic immunomodulatory effects for directly eradicating lymphatic metastases. This study elucidates a sophisticated lymph node immune-modulation strategy and provides a promising therapeutic approach to treat lymphatic metastasis. Advanced Science, EarlyView.