Tailored Liposomal Nanomedicine Suppresses Incomplete Radiofrequency Ablation‐Induced Tumor Relapse by Reprogramming Antitumor Immunity

Abstract Radiofrequency ablation (RFA), a thermoablative treatment for small hepatocellular carcinoma (HCC), has limited therapeutic benefit for advanced HCC patients with large, multiple, and/or irregular tumors owing to incomplete RFA (iRFA) of the tumor mass. It is first identified that iRFA‐treated tumors exhibited increased pyruvate kinase M2 (PKM2) expression, exacerbated tumor immunosuppression featured with increased tumor infiltration of suppressive immune cells and increased proliferation, and programmed cell death ligand 1 expression of cancer cell and ultimately a poor prognosis. Herein, a multifunctional nanomedicine is fabricated by encapsulating nanoassemblies of anti‐PD‐L1 and spermidine‐grafted oxidized dextran with shikonin‐containing lipid bilayers to reverse iRFA‐induced treatment failure. Shikonin, a PKM2 inhibitor, is used to suppress glycolysis in cancer cells, while anti‐PD‐L1 and spermidine are introduced to collectively reprogram the proliferation and functions of infiltrated CD8+ T lymphocytes. Combined with iRFA, which promoted the exposure of tumor antigens, the intravenous injection of liposomal SPS‐NPs effectively stimulated dendritic cell maturation and reversed tumor immunosuppression, thus eliciting potent antitumor immunity to synergistically suppress the growth of residual tumor masses and lung metastasis. The as‐prepared liposomal nanomedicine is promising for potentiating the therapeutic benefits of RFA toward advanced HCC patients through reprogramming iRFA‐induced tumor immunosuppression.