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.

尽管免疫检查点抑制剂（ICIs）等免疫治疗策略取得了有希望的进展，但其有限的疗效和显着的毒性仍然是肝细胞癌（HCC）免疫治疗的巨大挑战。T细胞浸润不足和免疫原性低的肿瘤免疫抑制微环境（TIME）是大多数HCC患者对ICIs反应不佳的原因。更糟糕的是，目前没有精确递送的免疫治疗可能会在临床上引起巨大的自身免疫副作用和全身毒性。随着对 HCC 中 TIME 的更好理解，纳米药物已成为一种有效的策略，通过靶向免疫治疗或多模式协同治疗来实现 TIME 重塑和超加性抗肿瘤效应。本文根据 HCC TIME 的典型特征，总结了基于纳米医学的 TIME 逆转 HCC 治疗策略的最新进展。此外，还对纳米药物在调节 HCC 时间方面面临的挑战和机遇提出了看法。获得纳米医学介导的时间逆转的知识将为研究人员提供更好的机会将肝癌免疫疗法应用于临床。