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

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.