Combination of exosome vaccines, lenvatinib, and anti-PD-1 eradicates tumor in autochthonous hepatocellular carcinoma mice.

Unresectable hepatocellular carcinoma (HCC) demands more effective therapeutics to overcome its dismal prognosis. Dendritic cell (DC)-derived exosomes (DEXs) modified with CP05-anchored HCC-targeting peptide (P47-P), DC-recruiting and -activating high-mobility group nucleosome-binding protein 1 (HMGN1) (N1ND-N), and lymphotactin domains (XCL1-X) make DEXPNX. In situ antigen release by oral lenvatinib (LEN) with intravenous DEXPNX (DEXPNX/LEN) synergistically promotes intratumoral DC recruitment and activation. This enhances tumor neoantigen cross-presentation, de novo T cell responses, and durable immunological memory against rechallenge in orthotopic HCC mice. Furthermore, DEXPNX/LEN suppresses tumor growth and increases tumor-infiltrating CD8+ T cells in diethyl-nitrosamine (DENA)-induced and non-alcoholic steatohepatitis-associated HCC mice. Crucially, combining DEXPNX/LEN with anti-PD-1 eradicates established tumor and boosts intratumoral CD8+ effector T cell expansion in autochthonous HCC mice. Our study demonstrates a generalizable strategy to elicit personalized antitumor responses by leveraging DEX vaccines to activate tumoral DCs against LEN-released antigens, strengthened by anti-PD-1 blocking T cell exhaustion. This represents a clinically viable approach to improve HCC outcomes.