Chemoimmunotherapy, which benefits from the combination of chemotherapy and immunotherapy, has emerged as a promising strategy in cancer treatment. However, effectively inducing a robust immune response remains challenging due to the limited responsiveness across patients. Endoplasmic reticulum (ER) stress is essential for activating intracellular signaling pathways associated with immunogenic cell death (ICD), targeting drugs to ER might enhance ER stress and improve ICD-related immunotherapy. To improve the immune response of Chemoimmunotherapy. ER targeting nanoparticles TSE-CEL/NP were constructed to enhance immunogenic cancer cell death. Flow cytometry, confocal microscope, TEM and immunofluorescence were used to evaluate the ER targeting effect and immunogenic tumor cell death on B16F10 tumor cells. Unilateral and bilateral tumor models were constructed to investigate the efficacy of anti-tumor and immunotherapy . Lung metastasis B16F10 melanoma tumor-bearing mice were used to assess the anti-metastasis efficacy. TSE-CEL/NP could specially accumulate in ER, thereby induce ER stress. High ER stress trigger the exposure of CRT, the extracellular release of HMGB1 and ATP. These danger signals subsequently promote the recruitment and maturation of dendritic cells (DCs), which in turn increase the proliferation of cytotoxic T lymphocytes (CD8 T cells), ultimately resulted in an improved immunotherapy efficacy against melanoma. experiments showed that TSE-CEL/NP exhibits excellent antitumor efficacy and triggers a strong immune response. Our findings demonstrated that celastrol ER targeting delivery could amplify immunogenic cell death in melanoma, which provide experimental basis for melanoma immunotherapy.

中文翻译：

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纳米颗粒介导的雷公藤红醇 ER 靶向递送放大黑色素瘤中的免疫原性细胞死亡


化学免疫疗法受益于化疗和免疫疗法的结合，已成为癌症治疗的一种有前景的策略。然而，由于患者的反应有限，有效诱导强大的免疫反应仍然具有挑战性。内质网 (ER) 应激对于激活与免疫原性细胞死亡 (ICD) 相关的细胞内信号通路至关重要，针对 ER 的药物可能会增强 ER 应激并改善 ICD 相关的免疫治疗。改善化学免疫疗法的免疫反应。构建 ER 靶向纳米粒子 TSE-CEL/NP 来增强免疫原性癌细胞死亡。采用流式细胞术、共聚焦显微镜、TEM和免疫荧光法评价ER对B16F10肿瘤细胞的靶向作用和免疫原性肿瘤细胞死亡。构建单侧和双侧肿瘤模型以研究抗肿瘤和免疫治疗的疗效。使用肺转移B16F10黑色素瘤荷瘤小鼠来评估抗转移功效。 TSE-CEL/NP可特异地积聚于内质网，从而诱发内质网应激。高 ER 应激会触发 CRT 暴露、HMGB1 和 ATP 的细胞外释放。这些危险信号随后促进树突状细胞 (DC) 的招募和成熟，进而增加细胞毒性 T 淋巴细胞 (CD8 T 细胞) 的增殖，最终提高针对黑色素瘤的免疫治疗效果。实验表明，TSE-CEL/NP表现出优异的抗肿瘤功效，并引发强烈的免疫反应。我们的研究结果表明，雷公藤红醇ER靶向递送可以放大黑色素瘤中的免疫原性细胞死亡，这为黑色素瘤免疫治疗提供了实验基础。