Zhu Susi, Zhang Xu, Liu Waner, Zhou Zhe, Xiong Siyu, Chen Xiang, Peng Cong
Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
J Exp Clin Cancer Res. 2025 Aug 27;44(1):255. doi: 10.1186/s13046-025-03521-5.
Melanoma, a highly aggressive and immunogenic skin cancer, often develops resistance to immunotherapy due to the immunosuppressive tumor microenvironment (TME). Although PD-1/PD-L1 inhibitors have significantly improved treatment outcomes, 30%-40% of patients exhibit no response or develop resistance. Mechanisms such as T-cell exhaustion within the TME limit therapeutic efficacy, necessitating the exploration of novel strategies to enhance immune responses.
This study evaluated the effects of Vinburnine (Vin) on melanoma cell proliferation, migration, invasion, apoptosis, and DNA damage through in vitro experiments. Transcriptomic analysis, Western blot, RT-PCR, dual-luciferase reporter assays, and ChIP experiments revealed the mechanism by which Vin regulates IL-24 via ATF3. The anti-tumor efficacy of Vin or IL-24 in combination with PD-1 monoclonal antibody, as well as their modulation of the tumor microenvironment, were validated through luciferase-mediated cytotoxicity assays and a murine melanoma model. Additionally, the correlation between IL-24 expression and patient prognosis or immunotherapy response was analyzed using public databases.
This study delineates the phenotypic mechanisms by which vinburnine suppresses melanoma proliferation. Vin induces reactive oxygen species (ROS) generation, leading to DNA damage and the subsequent activation of the apoptotic cascade in melanoma cells. Additionally, vinburnine activates the P38/MAPK/ATF3 signaling axis, which drives the secretion of interleukin-24 (IL-24), enhancing the functionality of CD8 T cells and modulating the tumor immune microenvironment to favor antitumor immunity. Notably, the combination of vinburnine with anti-PD-1 antibody therapy produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches.
These findings underscore the therapeutic potential of vinburnine, particularly when used in combination with immune checkpoint inhibitors, as a promising strategy for melanoma treatment.
黑色素瘤是一种极具侵袭性和免疫原性的皮肤癌，由于免疫抑制性肿瘤微环境（TME），其常常对免疫疗法产生耐药性。尽管PD-1/PD-L1抑制剂显著改善了治疗效果，但30%-40%的患者无反应或产生耐药性。TME内的T细胞耗竭等机制限制了治疗效果，因此需要探索增强免疫反应的新策略。
本研究通过体外实验评估了长春花碱（Vin）对黑色素瘤细胞增殖、迁移、侵袭、凋亡和DNA损伤的影响。转录组分析、蛋白质免疫印迹、逆转录聚合酶链反应、双荧光素酶报告基因检测和染色质免疫沉淀实验揭示了Vin通过激活转录因子3（ATF3）调控白细胞介素-24（IL-24）的机制。通过荧光素酶介导的细胞毒性检测和小鼠黑色素瘤模型验证了Vin或IL-24与PD-1单克隆抗体联合使用的抗肿瘤效果及其对肿瘤微环境的调节作用。此外，利用公共数据库分析了IL-24表达与患者预后或免疫治疗反应之间的相关性。
本研究阐述了长春花碱抑制黑色素瘤增殖的表型机制。Vin诱导活性氧（ROS）生成，导致DNA损伤，随后激活黑色素瘤细胞中的凋亡级联反应。此外，长春花碱激活P38/丝裂原活化蛋白激酶/ATF3信号轴，驱动白细胞介素-24（IL-24）的分泌，增强CD8 T细胞的功能，并调节肿瘤免疫微环境以利于抗肿瘤免疫。值得注意的是，长春花碱与抗PD-1抗体疗法联合使用产生协同效应，有效解决了当前免疫治疗方法的某些局限性。
这些发现强调了长春花碱的治疗潜力，特别是与免疫检查点抑制剂联合使用时，作为一种有前景的黑色素瘤治疗策略。
