<br>增强型光动力疗法与抑制肿瘤中性粒细胞铁死亡协同促进胃癌的抗 PD-1 疗法,Advanced Science

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增强型光动力疗法与抑制肿瘤中性粒细胞铁死亡协同促进胃癌的抗 PD-1 疗法
Advanced Science ( IF 14.3 ) Pub Date : 2024-01-17 , DOI: 10.1002/advs.202307870
Xudong Zhu ₁ , Wenxuan Zheng ₁ , Xingzhou Wang ₁ , Zhiyan Li ₁ , Xiaofei Shen ₁ , Qi Chen ₂ , Yanjun Lu ₁ , Kai Chen ₁ , Shichao Ai ₁ , Yun Zhu ₃ , Wenxian Guan ₁ , Shankun Yao ₄ , Song Liu ₁

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对于肿瘤治疗来说，肿瘤治疗的最终目标是消除原发肿瘤，控制潜在的转移，并引发抗肿瘤免疫反应，从而彻底清除所有恶性细胞。肿瘤微环境（TME）是指实体瘤的局部生物环境，已日益成为癌症治疗的一个有吸引力的靶点。胃癌 (GC) TME 内的中性粒细胞自发地发生铁死亡，该过程释放氧化脂质，限制 T 细胞活性。由二碘化 IR780 (Icy7) 介导的增强光动力疗法 (PDT) 显着增加活性氧 (ROS) 的产生。同时，TME 中 ROS 生成增加可引发中性粒细胞铁死亡。在这项研究中，封装铁死亡抑制剂Liproxstatin-1和修饰光敏剂Icy7（记为LLI）的脂质体显着抑制GC肿瘤生长。 LLI 内化至 MFC 细胞中，产生 ROS，导致免疫原性细胞死亡 (ICD)。同时，脂质体递送的 Liproxstatin-1 有效抑制肿瘤中性粒细胞的铁死亡。基于 LLI 的免疫原性 PDT 和中性粒细胞靶向免疫疗法可协同促进抗 PD-1 治疗，从而引发有效的 TME 和具有远隔效应的全身抗肿瘤免疫反应。总之，LLI 在 GC 免疫治疗方面具有巨大的潜力。

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Enhanced Photodynamic Therapy Synergizing with Inhibition of Tumor Neutrophil Ferroptosis Boosts Anti-PD-1 Therapy of Gastric Cancer

For tumor treatment, the ultimate goal in tumor therapy is to eliminate the primary tumor, manage potential metastases, and trigger an antitumor immune response, resulting in the complete clearance of all malignant cells. Tumor microenvironment (TME) refers to the local biological environment of solid tumors and has increasingly become an attractive target for cancer therapy. Neutrophils within TME of gastric cancer (GC) spontaneously undergo ferroptosis, and this process releases oxidized lipids that limit T cell activity. Enhanced photodynamic therapy (PDT) mediated by di-iodinated IR780 (Icy7) significantly increases the production of reactive oxygen species (ROS). Meanwhile, neutrophil ferroptosis can be triggered by increased ROS generation in the TME. In this study, a liposome encapsulating both ferroptosis inhibitor Liproxstatin-1 and modified photosensitizer Icy7, denoted LLI, significantly inhibits tumor growth of GC. LLI internalizes into MFC cells to generate ROS causing immunogenic cell death (ICD). Simultaneously, liposome-deliver Liproxstatin-1 effectively inhibits the ferroptosis of tumor neutrophils. LLI-based immunogenic PDT and neutrophil-targeting immunotherapy synergistically boost the anti-PD-1 treatment to elicit potent TME and systemic antitumor immune response with abscopal effects. In conclusion, LLI holds great potential for GC immunotherapy.

更新日期：2024-01-17

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