Song Haiqin, Montesdeoca Nicolás, Efanova Elizaveta, Li Xuan, Karges Johannes, Xiao Haihua, Shang Kun, Zhang Hanchen
Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200025, PR China.
Faculty of Chemistry and Biochemistry, Ruhr-University Bochum, Universitätsstrasse 150, 44780 Bochum, Germany.
J Control Release. 2025 Aug 10;384:113942. doi: 10.1016/j.jconrel.2025.113942. Epub 2025 Jun 9.
Immunotherapy has had a tremendous impact on cancer treatments. Although frequently used inside the clinics, the application of immunomodulating compounds remains restricted due to the immunosuppressive tumor microenvironment. Among the promising methods, the activation of the stimulator of interferon genes (STING) pathway has emerged as a next-generation immunotherapeutic target. Despite promising preliminary results, the application of STING activating agents is strongly limited due to poor tumor selectivity and poor bioavailability. To overcome these limitations, herein, the first example of a cobalt(III) cyclam prodrug capable of inducing a chemotherapeutic effect and activating the STING pathway is reported. The cobalt(III) complex was found to be stable under physiological conditions, but released its axial ligands within the reducing cancerous microenvironment. While the reduced metal complex triggered a strong cytotoxic response by chemotherapy, the released organic ligands induced a strong immune response using the STING pathway, resulting in a multimodal treatment. To further enhance the pharmacological properties and provide tumor selectivity, the metal complex was encapsulated in polymeric nanoparticles. Upon injection into the blood stream, the nanoparticles accumulated in the triple-negative breast cancer tumor of the mouse model, activated the immune response inside the animal, and caused a nearly complete eradication of the tumor.
免疫疗法对癌症治疗产生了巨大影响。尽管免疫调节化合物在临床中经常使用，但由于免疫抑制性肿瘤微环境，其应用仍然受到限制。在众多有前景的方法中，干扰素基因刺激物（STING）通路的激活已成为下一代免疫治疗靶点。尽管初步结果很有前景，但由于肿瘤选择性差和生物利用度低，STING激活剂的应用受到很大限制。为了克服这些限制，本文报道了首例能够诱导化疗效果并激活STING通路的钴（III）环胺前药。发现钴（III）配合物在生理条件下稳定，但在还原性癌微环境中释放其轴向配体。还原后的金属配合物通过化疗引发强烈的细胞毒性反应，而释放的有机配体利用STING通路诱导强烈的免疫反应，从而实现多模式治疗。为了进一步增强药理性质并提供肿瘤选择性，将金属配合物封装在聚合物纳米颗粒中。注入血流后，纳米颗粒在小鼠模型的三阴性乳腺癌肿瘤中积累，激活动物体内的免疫反应，并几乎完全消除肿瘤。
