Huang Yun, Wei Dengshuai, Wang Bin, Tang Dongsheng, Cheng Ailan, Xiao Shengjun, Yu Yingjie, Huang Weiguo
Guangxi Key Laboratory of Tumor Immunity and Microenvironment Regulation, Guilin Medical University, Guilin 541199, China; Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang 421001, China.
Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
Acta Biomater. 2023 Apr 1;160:198-210. doi: 10.1016/j.actbio.2023.02.012. Epub 2023 Feb 13.
As a DNA damaging agent, oxaliplatin (OXA) can induce immunogenic cell death (ICD) in tumors to activate the immune system. However, the DNA damage induced by OXA is limited and the ICD effect is not strong enough to enhance anti-tumor efficacy. Here, we propose a strategy to maximize the ICD effect of OXA through the mild hyperthermia generated by nanoparticles with a platinum (IV) prodrug of OXA (Pt(IV)-C16) and a near-infrared-II (NIR-II) photothermal agent IR1061 upon the irradiation of NIR-II light. The mild hyperthermia (43 °C) holds advantages in two aspects: 1) increase the Pt-DNA cross-linking, leading to enhanced DNA damage and apoptosis; 2) induce stronger ICD effects for cancer immunotherapy. We demonstrated that, compared with OXA and photothermal therapy of IR1061 alone, these nanoparticles under NIR-II light irradiation can significantly improve the anti-cancer efficacy against triple-negative breast cancer 4T1 tumor. This new strategy provides an effective way to improve the therapeutic outcome of OXA. STATEMENT OF SIGNIFICANCE: OXA could induce immunogenic cell death (ICD) via stimulating immune responses by increasing tumor cell stress and death, which triggers tumor-specific immune responses to achieve immunotherapy. However, due to the insufficient Pt-DNA crosslinks, the ICD effect triggered by OXA cannot induce robust immune response. Mild hyperthermia has great potential to maximize the therapeutic outcome of oxaliplatin by increasing the Pt-DNA cross-linking to augment the immunoresponse for enhanced cancer immunotherapy.
作为一种DNA损伤剂，奥沙利铂（OXA）可诱导肿瘤发生免疫原性细胞死亡（ICD）以激活免疫系统。然而，OXA诱导的DNA损伤有限，ICD效应不足以增强抗肿瘤疗效。在此，我们提出一种策略，通过由负载OXA的铂（IV）前药（Pt(IV)-C16）和近红外二区（NIR-II）光热剂IR1061组成的纳米颗粒在NIR-II光照射下产生的温和热疗，使OXA的ICD效应最大化。温和热疗（43°C）在两个方面具有优势：1）增加铂-DNA交联，导致DNA损伤和细胞凋亡增强；2）诱导更强的ICD效应用于癌症免疫治疗。我们证明，与单独使用OXA和IR1061的光热疗法相比，这些纳米颗粒在NIR-II光照射下可显著提高对三阴性乳腺癌4T1肿瘤的抗癌疗效。这一新策略为提高OXA的治疗效果提供了一种有效方法。重要性声明：OXA可通过增加肿瘤细胞应激和死亡来刺激免疫反应，从而诱导免疫原性细胞死亡（ICD），进而触发肿瘤特异性免疫反应以实现免疫治疗。然而，由于铂-DNA交联不足,OXA触发的ICD效应无法诱导强大的免疫反应。温和热疗通过增加铂-DNA交联以增强免疫反应从而提高癌症免疫治疗效果，具有极大潜力使奥沙利铂的治疗效果最大化。
