Rashid Mohsen, Ramezani Mina, Molavi Ommoleila, Ghesmati Zeinab, Baradaran Behzad, Sabzichi Mehdi, Ramezani Fatemeh
Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Bioimpacts. 2024 Sep 10;15:30424. doi: 10.34172/bi.30424. eCollection 2025.
The immunosuppressive context of the tumor microenvironment (TME) is a significant hurdle in breast cancer (BC) treatment. Combinational therapies targeting cancer core signaling pathways involved in the induction of TME immunosuppressive milieu have emerged as a potent strategy to overcome immunosuppression in TME and enhance patient therapeutic outcomes. This study presents compelling evidence that targeting hypoxia-inducible-factor-1 alpha (Hif-1α) alongside chemotherapy and immune-inducing factors leads to substantial anticancer effects through modulation of TME.
Chitosan (Cs)/Hif-1alpha siRNA nano-complex was synthesized by siRNA adsorption methods. Nanoparticles were fully characterized using dynamic light scattering and scanning electron microscope. Cs/Hif-1α siRNA cytotoxicity was measured by MTT assay. The anticancer effects of the combinational therapy were assessed in BALB/c bearing 4T1 tumors. qPCR and western blotting were applied to assess the expression of some key genes and proteins involved in the induction of immunosuppression in TME.
Hif-1α siRNA was successfully loaded in chitosan nanoparticles. Hif-1α siRNA nanocomplexes significantly inhibited the expression of . Triple combination therapy (Paclitaxel (Ptx) + Imiquimod (Imq) + Cs/Hif-1α siRNA) inhibited tumor growth and downregulated cancer progression genes while upregulating cellular-immune-related cytokines. Mice without Cs/Hif-1α siRNA treatments revealed fewer cancer inhibitory effects and more TME immunosuppressive factors. These results suggest that the inhibition of effects synergize with Ptx and Imq to inhibit cancer progression more significantly than other combinational treatments.
Combining Hif-1α siRNA with Ptx and Imq is promising as a multimodality treatment. It has the potential to attenuate TME inhibitory effects and significantly enhance the immune system's ability to combat tumor cell growth, offering an inspiration of hope in the fight against BC.
肿瘤微环境（TME）的免疫抑制背景是乳腺癌（BC）治疗中的一个重大障碍。针对参与诱导TME免疫抑制环境的癌症核心信号通路的联合疗法已成为克服TME免疫抑制并提高患者治疗效果的有效策略。本研究提供了令人信服的证据，表明在化疗和免疫诱导因子的基础上靶向缺氧诱导因子-1α（Hif-1α）可通过调节TME产生显著的抗癌效果。
通过siRNA吸附法合成壳聚糖（Cs）/Hif-1α siRNA纳米复合物。使用动态光散射和扫描电子显微镜对纳米颗粒进行全面表征。通过MTT法测定Cs/Hif-1α siRNA的细胞毒性。在携带4T1肿瘤的BALB/c小鼠中评估联合疗法的抗癌效果。应用qPCR和蛋白质印迹法评估TME中参与免疫抑制诱导的一些关键基因和蛋白质的表达。
Hif-1α siRNA成功负载于壳聚糖纳米颗粒中。Hif-1α siRNA纳米复合物显著抑制了 的表达。三联联合疗法（紫杉醇（Ptx）+咪喹莫特（Imq）+Cs/Hif-1α siRNA）抑制肿瘤生长并下调癌症进展基因，同时上调细胞免疫相关细胞因子。未接受Cs/Hif-1α siRNA治疗的小鼠显示出较少的癌症抑制作用和更多的TME免疫抑制因子。这些结果表明，对 效应的抑制与Ptx和Imq协同作用，比其他联合治疗更显著地抑制癌症进展。
将Hif-1α siRNA与Ptx和Imq联合作为一种多模态治疗方法具有前景。它有可能减弱TME的抑制作用，并显著增强免疫系统对抗肿瘤细胞生长的能力，为抗击BC提供了希望的启示。
