Yang Huajing, Li Rui, Jin Shiyang, Tian Yuhang, Wang Chunyue, Sun Yucao, Dai Zhifei, Cheng Wen
Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150081, China.
Department of Biomedical Engineering, College of Future Technology, National Biomedical Imaging Center, Peking University, Beijing 100871, China.
Acta Biomater. 2025 Jun 1;199:387-397. doi: 10.1016/j.actbio.2025.05.029. Epub 2025 May 9.
Hepatocellular carcinoma (HCC) is the most common primary malignant disease of the liver. Although immunotherapy offers new opportunities for treating advanced HCC, its therapeutic effect is still limited by the immunosuppressive tumor microenvironment (TME). Herein, a nanosensitizer RGD@Ce6@MSA-2@Liposome (RCM-Lip) is synthesized to specifically initiate the HCC tumor immune microenvironment through sonodynamic therapy (SDT)-triggered immunogenic cell death (ICD) and MSA-2-activated cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. RCM-Lip consists of a sonosensitizer (Chlorin e6, Ce6) with a STING agonist (MSA-2) and a tumor targeting peptide RGD inserted on the outer liposome surface. Under ultrasound irradiation, RCM-Lip generates reactive oxygen species that induce cytotoxicity and apoptosis of tumor cells. Meanwhile, tumor antigens released by apoptosis are taken up by dendritic cells (DCs), while STING is activated in the DCs by MSA-2. Moreover, DC maturation is stimulated, further enhancing the systematic anti-tumor immune responses. Sono-immunotherapy mediated by RCM-Lip promotes DCs maturation and tumor infiltration of CD8T cells, increasing inflammatory cytokine secretion. Consequently, the immunologically "cold" TME of HCC is successfully turned into a "hot" one, leading to a significant tumor suppression effect with good bio-safety. These results suggest a promising method for precise tumor targeting and synergistic cancer sono-immunotherapy. STATEMENT OF SIGNIFICANCE: Our study addressed the therapeutic dilemma of hepatocellular carcinoma (HCC) as an immunological "cold" tumor by the synergistic application of sonodynamic therapy (SDT) and STING agonist. The cGAS-STING signaling pathway plays a pivotal role in innate immunity against cancer, but the clinical application of STING agonists were hampered by inflammatory responses due to off-target activation. Our innovative solution introduces RGD-targeted peptide to encapsulate sonosensitizer and STING agonist, strengthening therapeutic effects and reducing systemic toxicity. The targeted sono-immunotherapy promoted DCs maturation and tumor infiltration of CD8T cells, producing intense tumor-killing effect on mice model with good bio-safety. As a result, the immunological "cold" tumor microenvironment of HCC is successfully turned into a "hot" one.
肝细胞癌（HCC）是肝脏最常见的原发性恶性疾病。尽管免疫疗法为治疗晚期HCC提供了新的机会，但其治疗效果仍受免疫抑制性肿瘤微环境（TME）的限制。在此，合成了一种纳米敏化剂RGD@Ce6@MSA-2@脂质体（RCM-Lip），通过声动力疗法（SDT）触发的免疫原性细胞死亡（ICD）和MSA-2激活的环鸟苷酸-腺苷酸合成酶（cGAS）-干扰素基因刺激物（STING）途径特异性启动HCC肿瘤免疫微环境。RCM-Lip由一种声敏剂（二氢卟吩e6，Ce6）、一种STING激动剂（MSA-2）和一个插入在外脂质体表面的肿瘤靶向肽RGD组成。在超声照射下，RCM-Lip产生活性氧，诱导肿瘤细胞的细胞毒性和凋亡。同时，凋亡释放的肿瘤抗原被树突状细胞（DCs）摄取，而STING在DCs中被MSA-2激活。此外，刺激DC成熟，进一步增强系统性抗肿瘤免疫反应。由RCM-Lip介导的声动力免疫疗法促进DC成熟和CD8T细胞的肿瘤浸润，增加炎性细胞因子分泌。因此，HCC的免疫“冷”TME成功转变为“热”TME，产生显著的肿瘤抑制作用且生物安全性良好。这些结果提示了一种用于精确肿瘤靶向和协同癌症声动力免疫疗法的有前景的方法。重要性声明：我们的研究通过声动力疗法（SDT）和STING激动剂的协同应用解决了肝细胞癌（HCC）作为免疫“冷”肿瘤的治疗困境。cGAS-STING信号通路在针对癌症的先天免疫中起关键作用，但STING激动剂的临床应用因脱靶激活引起的炎症反应而受到阻碍。我们的创新解决方案引入RGD靶向肽来包裹声敏剂和STING激动剂，增强治疗效果并降低全身毒性。靶向声动力免疫疗法促进DC成熟和CD8T细胞的肿瘤浸润，对小鼠模型产生强烈的肿瘤杀伤作用且生物安全性良好。结果，HCC的免疫“冷”肿瘤微环境成功转变为“热”微环境。
