肿瘤细胞治疗研究
英文原题：Photosensitive small extracellular vesicles regulate the immune microenvironment of triple negative breast cancer.
目前，三阴性乳腺癌（TNBC）的治疗受限于该疾病特殊的病理特征。
目前，三阴性乳腺癌（TNBC）的治疗受到该疾病特殊病理特征的限制。近年来，光动力疗法（PDT）为TNBC的治疗带来了新的希望。此外，PDT可诱导免疫原性细胞死亡（ICD）并提高肿瘤免疫原性。然而，尽管PDT能够提高TNBC的免疫原性，TNBC的抑制性免疫微环境仍会削弱抗肿瘤免疫应答。因此，我们使用中性鞘磷脂酶抑制剂GW4869抑制TNBC细胞分泌小细胞外囊泡（sEVs），以改善肿瘤免疫微环境并增强抗肿瘤免疫。此外，骨髓间充质干细胞（BMSC）来源的sEVs具有良好的生物安全性和较强的载药能力，可有效提高药物递送效率。在本研究中，我们首先获取了原代BMSCs和sEVs，然后通过电穿孔将光敏剂Ce6和GW4869载入sEVs中，制备免疫调节光敏纳米囊泡（Ce6-GW4869/sEVs）。当给予TNBC细胞或原位TNBC模型时，这些光敏sEVs能够特异性靶向TNBC并改善肿瘤免疫微环境。此外，PDT联合基于GW4869的治疗通过直接杀伤TNBC和激活抗肿瘤免疫表现出强效的协同抗肿瘤作用。在此，我们设计了能够靶向TNBC并调节肿瘤免疫微环境的光敏sEVs，为提高TNBC治疗效果提供了一种潜在途径。意义声明：我们设计了一种免疫调节光敏纳米囊泡（Ce6-GW4869/sEVs），其中光敏剂Ce6用于实现光动力治疗，中性鞘磷脂酶抑制剂GW4869用于抑制三阴性乳腺癌（TNBC）细胞分泌小细胞外囊泡（sEVs），从而改善肿瘤免疫微环境并增强抗肿瘤免疫。在本研究中，该免疫调节光敏纳米囊泡能够靶向TNBC细胞并调节肿瘤免疫微环境，从而为改善TNBC治疗效果提供了一种潜在策略。我们发现，GW4869诱导的肿瘤sEVs分泌减少改善了肿瘤抑制性免疫微环境。此外，类似的治疗策略也可应用于其他类型的肿瘤，尤其是免疫抑制性肿瘤，这对肿瘤免疫治疗的临床转化具有重要价值。
Currently, the treatment of triple-negative breast cancer (TNBC) is limited by the special pathological characteristics of this disease. In recent years, photodynamic therapy (PDT) has created new hope for the treatment of TNBC. Moreover, PDT can induce immunogenic cell death (ICD) and improve tumor immunogenicity. However, even though PDT can improve the immunogenicity of TNBC, the inhibitory immune microenvironment of TNBC still weakens the antitumor immune response. Therefore, we used the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by TNBC cells to improve the tumor immune microenvironment and enhance antitumor immunity. In addition, bone mesenchymal stem cell (BMSC)-derived sEVs have good biological safety and a strong drug loading capacity, which can effectively improve the efficiency of drug delivery. In this study, we first obtained primary BMSCs and sEVs, and then the photosensitizers Ce6 and GW4869 were loaded into the sEVs by electroporation to produce immunomodulatory photosensitive nanovesicles (Ce6-GW4869/sEVs). When administered to TNBC cells or orthotopic TNBC models, these photosensitive sEVs could specifically target TNBC and improve the tumor immune microenvironment. Moreover, PDT combined with GW4869-based therapy showed a potent synergistic antitumor effect mediated by direct killing of TNBC and activation of antitumor immunity. Here, we designed photosensitive sEVs that could target TNBC and regulate the tumor immune microenvironment, providing a potential approach for improving the effectiveness of TNBC treatment. STATEMENT OF SIGNIFICANCE: We designed an immunomodulatory photosensitive nanovesicle (Ce6-GW4869/sEVs) with the photosensitizer Ce6 to achieve photodynamic therapy and the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by triple-negative breast cancer (TNBC) cells to improve the tumor immune microenvironment and enhance antitumor immunity. In this study, the immunomodulatory photosensitive nanovesicle could target TNBC cells and regulate the tumor immune microenvironment, thus providing a potential approach for improving the treatment effect in TNBC. We found that the reduction in tumor sEVs secretion induced by GW4869 improved the tumor-suppressive immune microenvironment. Moreover, similar therapeutic strategies can also be applied in other kinds of tumors, especially immunosuppressive tumors, which is of great value for the clinical translation of tumor immunotherapy.
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