Nanomedicines for reversing immunosuppressive microenvironment of hepatocellular carcinoma

Although immunotherapeutic strategies such as immune checkpoint inhibitors (ICIs) have gained promising advances, their limited efficacy and significant toxicity remain great challenges for hepatocellular carcinoma (HCC) immunotherapy. The tumor immunosuppressive microenvironment (TIME) with insufficient T-cell infiltration and low immunogenicity accounts for most HCC patients' poor response to ICIs. Worse still, the current immunotherapeutics without precise delivery may elicit enormous autoimmune side effects and systemic toxicity in the clinic. With a better understanding of the TIME in HCC, nanomedicines have emerged as an efficient strategy to achieve remodeling of the TIME and superadditive antitumor effects via targeted delivery of immunotherapeutics or multimodal synergistic therapy. Based on the typical characteristics of the TIME in HCC, this review summarizes the recent advancements in nanomedicine-based strategies for TIME-reversing HCC treatment. Additionally, perspectives on the awaiting challenges and opportunities of nanomedicines in modulating the TIME of HCC are presented. Acquisition of knowledge of nanomedicine-mediated TIME reversal will provide researchers with a better opportunity for clinical translation of HCC immunotherapy.