Extracellular vesicle-mediated co-delivery of FSL-1 and LY2157299 for immunotherapy of small-cell lung cancer liver metastases

Small-cell lung cancer (SCLC) frequently metastasizes to the liver, where macrophage‑dominated immunosuppression sustains tumor outgrowth. Bioinformatic analyses of SCLC liver metastases implicate macrophage metabolism as a driver of hepatic progression. We engineered extracellular vesicles (EVs) co‑delivering FSL‑1 (TLR2/6 agonist) and LY2157299/galunisertib (TGF‑betaRI inhibitor) to reprogram macrophages. In vitro, dual‑loaded EVs more efficiently shifted macrophages toward pro‑inflammatory, antigen‑presenting states. In vivo, EVs efficiently targeted intrahepatic tumor sites, decreased liver tumor growth, and prolonged mouse survival. These data support EV‑mediated co‑delivery of FSL‑1 and LY2157299 as a macrophage‑centric strategy for SCLC liver metastasis.