School of Pharmacy, Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai 264003, PR China.
Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, PR China.
Acta Biomater. 2024 Aug;184:383-396. doi: 10.1016/j.actbio.2024.06.025. Epub 2024 Jun 25.
Triple-negative breast cancer (TNBC) is a relatively "cold" tumour with low immunogenicity compared to other tumour types. Especially, the immune checkpoint inhibitors to treat metastatic TNBC only shows the modest immune response rates. Here, we used Chlorella vulgaris as a bioreactor to synthesize an efficient nanobomb (Bio-MnSe) aimed at eliciting systemic anti-tumour immune response. Despite possessing extremely low Mn content, Bio-MnSe effectively produced more ROS and activated stronger cGAS-STING signal pathway compared to pure Se nanoparticles and free Mn ions, promoting the infiltration of natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) in tumour, effectively turning "cold" tumour into "hot" tumour, and achieving strong antitumour immunotherapy. Additionally, the use of αPD-L1 as an immune checkpoint antagonist further increased the anti-tumour immune response of Bio-MnSe, resulting in enhanced anti-tumour effects. Doxorubicin (Dox), an immunogenic cell death (ICD) inducer, was combined with Bio-MnSe to form Bio-MnSe@Dox. This Bio-MnSe@Dox not only directly damaged tumour cells and induced tumour ICD but also promoted dendritic cell maturation, cytotoxic T lymphocyte infiltration, and NK cell recruitment, synergistically intensifying anti-tumour immune responses and suppressing tumour relapse and lung metastasis. Collectively, our findings propose an effective strategy for transforming 'cold' tumours to 'hot' ones, thereby advancing the development of anti-tumour immune drugs. STATEMENT OF SIGNIFICANCE: A biogenic MnSe (Bio-MnSe) nanocomposite was synthesized using Chlorella vulgaris as a bioreactor for enhanced immunotherapy of TNBC. Bio-MnSe demonstrated a stronger ability to activate the cGAS-STING signalling pathway and generate more ROS compared to pure Se nanoparticles and free Mn ions. Apoptotic cells induced by Bio-MnSe released a significant amount of interferon, leading to the activation of T and natural killer (NK) cells, ultimately transforming immunologically 'cold' breast tumours to 'hot' tumours and enhancing the tumour's response to immune checkpoint inhibitors. The combination of Bio-MnSe with Dox or αPD-L1 further enhanced the anti-tumour immune response, fostering dendritic cell maturation, infiltration of cytotoxic T lymphocytes, and recruitment of NK cells, thereby enhancing the anti-tumour immunotherapy of TNBC.
三阴性乳腺癌(TNBC)与其他肿瘤类型相比,免疫原性较低,是一种相对“冷”的肿瘤。特别是,用于治疗转移性 TNBC 的免疫检查点抑制剂仅显示出适度的免疫反应率。在这里,我们使用普通小球藻作为生物反应器来合成一种有效的纳米炸弹(Bio-MnSe),旨在引发全身性抗肿瘤免疫反应。尽管 Bio-MnSe 中 Mn 的含量极低,但与纯硒纳米颗粒和游离 Mn 离子相比,它有效地产生了更多的 ROS,并激活了更强的 cGAS-STING 信号通路,促进了自然杀伤(NK)细胞、细胞毒性 T 淋巴细胞(CTLs)在肿瘤中的浸润,有效地将“冷”肿瘤转化为“热”肿瘤,实现了强大的抗肿瘤免疫治疗。此外,使用 αPD-L1 作为免疫检查点拮抗剂进一步增强了 Bio-MnSe 的抗肿瘤免疫反应,从而增强了抗肿瘤效果。阿霉素(Dox)是一种免疫原性细胞死亡(ICD)诱导剂,与 Bio-MnSe 结合形成 Bio-MnSe@Dox。这种 Bio-MnSe@Dox 不仅直接损伤肿瘤细胞并诱导肿瘤 ICD,还促进树突状细胞成熟、CTL 浸润和 NK 细胞募集,协同增强抗肿瘤免疫反应,抑制肿瘤复发和肺转移。总之,我们的研究结果提出了一种将“冷”肿瘤转化为“热”肿瘤的有效策略,从而推进抗肿瘤免疫药物的发展。
Cell Oncol (Dordr). 2025-5-21