Targeted Inhibition of Tumor Extracellular Vesicle Secretion Improving the Anti‐Tumor Immunity of Lymph Node‐Targeted Vaccines

Abstract The combined immunotherapy of tumor vaccine and immune checkpoint blockade (ICB) has shown promising therapeutic benefits in tumor treatment. Notably, the off‐target effects of immune checkpoint inhibitors and their immune‐related adverse events (irAEs) seriously affect the therapeutic outcome of ICB. Tumor extracellular vesicles (EVs) can exacerbate the immunosuppressive microenvironment through complex mechanisms, further impacting anti‐tumor immunity. Herein, an EV secretion inhibitor, GW4869‐loaded platform named G@L‐3 is developed, and this platform can selectively deliver GW4869 to tumor tissues through homologous targeting of tumor cell membranes and further efficiently inhibit tumor EV secretion. The downregulation of tumor EV in circulation endows the improvement of immunosuppressive microenvironment by the reduction of PDL1, TGF‐β1, and IL‐10. Meanwhile, the chimeric vesicle vaccine Hybrid NVs is prepared, and this platform enables the efficient delivery of tumor antigens to lymph nodes through the inherent property of the M1 macrophage membrane. Remarkably, the effector function of T cells is significantly reshaped by the combined use of G@L‐3 and Hybrid NVs in the manner of sequential immunization, further exerting robust tumor killing and tumor metastasis inhibition. Collectively, an innovative combined immunotherapy has been developed and has demonstrated its safety and effectiveness.