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

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.