Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma

作者：Junfeng Liu, Xi Li, J. Chen, Jingpei Guo, Hui Guo, Xiaoting Zhang, Jinming Fan, Ke Zhang, Junjie Mao, Bin Zhou · 发表于：Journal of Nanobiotechnology · 年份：2024 · DOI：10.1186/s12951-024-02579-1 · 被引用次数：21 · 研究领域：Hepatocellular Carcinoma Treatment and Prognosis、Nanoplatforms for cancer theranostics、Cancer, Hypoxia, and Metabolism

BACKGROUND: Incomplete radiofrequency ablation (iRFA) in hepatocellular carcinoma (HCC) often leads to local recurrence and distant metastasis of the residual tumor. This is closely linked to the development of a tumor immunosuppressive environment (TIME). In this study, underlying mechanisms and potential therapeutic targets involved in the formation of TIME in residual tumors following iRFA were explored. Then, TAK-981-loaded nanocomposite hydrogel was constructed, and its therapeutic effects on residual tumors were investigated. RESULTS: This study reveals that the upregulation of small ubiquitin-like modifier 2 (Sumo2) and activated SUMOylation is intricately tied to immunosuppression in residual tumors post-iRFA. Both knockdown of Sumo2 and inhibiting SUMOylation with TAK-981 activate IFN-1 signaling in HCC cells, thereby promoting dendritic cell maturation. Herein, we propose an injectable PDLLA-PEG-PDLLA (PLEL) nanocomposite hydrogel which incorporates self-assembled TAK-981 and BSA nanoparticles for complementary localized treatment of residual tumor after iRFA. The sustained release of TAK-981 from this hydrogel curbs the expansion of residual tumors and notably stimulates the dendritic cell and cytotoxic lymphocyte-mediated antitumor immune response in residual tumors while maintaining biosafety. Furthermore, the treatment with TAK-981 nanocomposite hydrogel resulted in a widespread elevation in PD-L1 levels. Combining TAK-981 nanocomposite hydrogel with PD-L1 block...