铂类配合物在恶性肿瘤化疗-免疫治疗策略中作用机制及其研究进展  

Advances of platinum-based complexes in chemo-immunotherapy strategies for malignant tumor

作　　者：葛晓 李珊 罗雅瑄 张琦琛 陈飞虹 GE Xiao;LI Shan;LUO Ya-xuan;ZHANG Qi-chen;CHEN Fei-hong(School of Chemistry and Chemical Engineering,Southeast University,Nanjing 21l189,China)

机构地区：[1]东南大学化学化工学院,江苏南京211189

出　　处：《药学学报》2025年第3期667-678,共12页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金面上资助项目(82173852)。

摘　　要：铂类配合物,尤其是二价铂[platinum(II),Pt(II)]化合物,已经成为治疗恶性肿瘤的经典化疗方案。由于其稳定性不足、容易诱发获得性耐药和强烈的细胞毒性,限制了其在临床中的广泛应用。尽管干扰程序性死亡蛋白1(programmed cell death protein 1,PD-1)/程序性死亡配体1(programmed cell death protein 1,PD-1)相互作用的抗体与铂类配合物联合免疫疗法在抗癌治疗中取得了显著的临床进展,但其高效性往往伴随显著的毒性和免疫相关不良反应,限制了其长期应用。相比之下,四价铂[platinum(IV),Pt(IV)]配合物凭借其独特的八面体几何结构,展现出较好的抗癌潜力。通过修饰其轴向配体,Pt(IV)配合物不仅具有更高的惰性和更好的肿瘤选择性,还能够在靶向肿瘤微环境时以特定方式释放轴向配体。这一机制赋予其克服耐药性、减少毒性并增强免疫系统激活的能力,使其成为当下抗癌领域的研究热点。更重要的是,Pt(IV)配合物能够通过多种途径实现抗肿瘤效果,包括通过触发DNA损伤诱导肿瘤细胞发生凋亡、自噬和铁死亡。该多重作用机制不仅增强了抗肿瘤效力,还显著减少了传统铂类配合物的不良反应。本文总结了铂类配合物,特别是Pt(IV)配合物在化疗-免疫联合治疗中的抗肿瘤作用机制,探讨了其在抗肿瘤治疗中的潜力,为开发高效、低毒、靶向性强的Pt(IV)配合物提供了理论支持。Platinum-based complexes,particularly divalent platinum[platinum(II),Pt(II)]compounds,have become classic chemotherapy agents for the treatment of malignant tumors.However,their widespread clinical use is limited due to issues such as insufficient stability,the induction of acquired resistance and strong cytotoxicity.Although antibodies that interfere with the interaction between programmed cell death protein 1(PD-1)and programmed cell death ligand 1(PD-L1),in combination with platinum-based compounds,have shown significant clinical progress in cancer treatment,their high efficacy is often accompanied by substantial toxicity and immunerelated side effects,which limit their long-term use.In contrast,platinum(IV)[Pt(IV)]complexes,with their unique octahedral geometry,have demonstrated promising anticancer potential.By modifying the axial ligands,Pt(IV)-based complexes not only show higher inertness and improved tumor selectivity,but also enable the targeted release of active ligands in the tumor microenvironment.The mechanism allows Pt(IV)-based complexes to overcome drug resistance,reduce toxicity and enhance immune system activation,making them a research hotspot in the current cancer field.More importantly,Pt(IV)-based complexes can exert anticancer effects through multiple pathways including causing DNA damage to trigger apoptosis,autophagy and ferroptosis in tumor cells.This multifaceted action mechanism not only enhances antitumor efficacy but also significantly reduces side effects associated with traditional platinum-based compounds.This review summarizes whole anticancer mechanisms of platinum-based complexes,particularly Pt(IV)complexes in chemo-immunetherapy combination therapies,discussing their potential in cancer treatment and providing theoretical support for the development of efficient,low-toxicity and highly selective Pt(IV)-based complexes.

关 键 词：铂类配合物 肿瘤化疗-免疫治疗 抗肿瘤机制 耐药性 恶性肿瘤 

分 类 号：R966[医药卫生—药理学]