Injectable thermosensitive microsphere-hydrogel composite system: combined therapy of hepatocellular carcinoma by remodeling tumor immune microenvironment

Advanced hepatocellular carcinoma (HCC) is one of the most prevalent malignancies, and the clinical treatment outcomes are not satisfactory. Due to the complexity, heterogeneity, and immunosuppressive microenvironment of HCC, monotherapies have limited effects. Therefore, combined therapy may effectively enhance antitumor treatment by remodeling the tumor immune microenvironment. This study reports an injectable thermosensitive microsphere-hydrogel composite system for local co-delivery of the targeted drug sorafenib (SOR) and immunomodulatory cytokines for the combined therapy of HCC. The delivery system exhibited superior properties such as dual-drug delivery, sustained and slow release, local injectability, thermosensitivity, and low side effects. Moreover, it successfully remodeled the immune microenvironment of HCC by increasing the infiltration of CD8⁺ T cells and natural killer cells while decreasing the infiltration of immunosuppressive Treg cells, thereby achieving a potent synergistic effect with SOR. This safe composite delivery system can remodel the tumor microenvironment and enhance anti-tumor treatment, providing a valuable option for the treatment of HCC.