PDF(Pubmed)
Abstract：
BACKGROUND: Sunitinib is a multikinase inhibitor used to treat patients with advanced renal cell carcinoma (RCC). However, sunitinib toxicity makes it a double-edged sword. Potent immune modulation by sunitinib extends to nuclear interactions. To address these issues, there is an urgent need for delivery vectors suitable for sunitinib treatment.
METHODS: We developed PEGylated liposomes as delivery vectors to precisely target sunitinib (lipo-sunitinib) to RCC tumors. Further investigations, including RNA sequencing (RNA-seq), were performed to evaluate transcriptomic changes in these pathways. DiI/DiR-labeled lipo-sunitinib was used for the biodistribution analysis. Flow cytometry and immunofluorescence (IF) were used to examine immune modulation in orthotopic RCC models.
RESULTS: The evaluation of results indicated that lipo-sunitinib precisely targeted the tumor site to induce autophagy and was readily taken up by RCC tumor cells. In addition, transcriptomic assays revealed that following lipo-sunitinib treatment, autophagy, antigen presentation, cytokine, and chemokine production pathways were upregulated, whereas the epithelial-mesenchymal transition (EMT) pathway was downregulated. In vivo data provided evidence supporting the inhibitory effect of lipo-sunitinib on RCC tumor progression and metastasis. Flow cytometry further demonstrated that liposunitinib increased the infiltration of effector T cells (Teffs) and conventional type 1 dendritic cells (cDC1s) into the tumor. Furthermore, systemic immune organs such as the tumor-draining lymph nodes, spleen, and bone marrow exhibited upregulated anticancer immunity following lipo-sunitinib treatment.
CONCLUSIONS: Our findings demonstrated that lipo-sunitinib is distributed at the RCC tumor site, concurrently inducing potent autophagy, elevating antigen presentation, activating cytokine and chemokine production pathways, and downregulating EMT in RCC cells. This comprehensive approach significantly enhanced tumor inhibition and promoted anticancer immune modulation.
METHODS: We developed PEGylated liposomes as delivery vectors to precisely target sunitinib (lipo-sunitinib) to RCC tumors. Further investigations, including RNA sequencing (RNA-seq), were performed to evaluate transcriptomic changes in these pathways. DiI/DiR-labeled lipo-sunitinib was used for the biodistribution analysis. Flow cytometry and immunofluorescence (IF) were used to examine immune modulation in orthotopic RCC models.
RESULTS: The evaluation of results indicated that lipo-sunitinib precisely targeted the tumor site to induce autophagy and was readily taken up by RCC tumor cells. In addition, transcriptomic assays revealed that following lipo-sunitinib treatment, autophagy, antigen presentation, cytokine, and chemokine production pathways were upregulated, whereas the epithelial-mesenchymal transition (EMT) pathway was downregulated. In vivo data provided evidence supporting the inhibitory effect of lipo-sunitinib on RCC tumor progression and metastasis. Flow cytometry further demonstrated that liposunitinib increased the infiltration of effector T cells (Teffs) and conventional type 1 dendritic cells (cDC1s) into the tumor. Furthermore, systemic immune organs such as the tumor-draining lymph nodes, spleen, and bone marrow exhibited upregulated anticancer immunity following lipo-sunitinib treatment.
CONCLUSIONS: Our findings demonstrated that lipo-sunitinib is distributed at the RCC tumor site, concurrently inducing potent autophagy, elevating antigen presentation, activating cytokine and chemokine production pathways, and downregulating EMT in RCC cells. This comprehensive approach significantly enhanced tumor inhibition and promoted anticancer immune modulation.
摘要：
背景：舒尼替尼是一种多激酶抑制剂，用于治疗晚期肾细胞癌（RCC）患者。然而,舒尼替尼的毒性使其成为一把双刃剑。舒尼替尼的有效免疫调节延伸至核相互作用。为了解决这些问题,迫切需要适用于舒尼替尼治疗的递送载体.
方法：我们开发了聚乙二醇化脂质体作为递送载体，将舒尼替尼（lipo-sunitinib）精确靶向RCC肿瘤。进一步调查,包括RNA测序（RNA-seq），进行评估这些途径的转录组变化。使用DiI/DiR标记的脂-舒尼替尼进行生物分布分析。流式细胞术和免疫荧光（IF）用于检查原位RCC模型中的免疫调节。
结果：结果评价表明，lipo-sunitinib精确靶向肿瘤部位诱导自噬，容易被RCC肿瘤细胞吸收。此外,转录组学分析显示，在lipo-sunitinib治疗后，自噬,抗原呈递,细胞因子,趋化因子产生途径上调，而上皮-间质转化（EMT）途径下调。体内数据提供了证据支持lipo-sunitinib对RCC肿瘤进展和转移的抑制作用。流式细胞术进一步证明脂质体unitinib增加了效应T细胞(Teffs)和常规1型树突状细胞(cDC1s)向肿瘤的浸润。此外，全身免疫器官，如肿瘤引流淋巴结，脾,脾lipo-sunitinib治疗后，骨髓显示抗癌免疫力上调。
结论：我们的研究结果表明，lipo-sunitinib分布在RCC肿瘤部位，同时诱导有效的自噬，升高抗原呈递，激活细胞因子和趋化因子产生途径，并下调RCC细胞中的EMT。这种综合方法显着增强了肿瘤抑制作用并促进了抗癌免疫调节。
方法：我们开发了聚乙二醇化脂质体作为递送载体，将舒尼替尼（lipo-sunitinib）精确靶向RCC肿瘤。进一步调查,包括RNA测序（RNA-seq），进行评估这些途径的转录组变化。使用DiI/DiR标记的脂-舒尼替尼进行生物分布分析。流式细胞术和免疫荧光（IF）用于检查原位RCC模型中的免疫调节。
结果：结果评价表明，lipo-sunitinib精确靶向肿瘤部位诱导自噬，容易被RCC肿瘤细胞吸收。此外,转录组学分析显示，在lipo-sunitinib治疗后，自噬,抗原呈递,细胞因子,趋化因子产生途径上调，而上皮-间质转化（EMT）途径下调。体内数据提供了证据支持lipo-sunitinib对RCC肿瘤进展和转移的抑制作用。流式细胞术进一步证明脂质体unitinib增加了效应T细胞(Teffs)和常规1型树突状细胞(cDC1s)向肿瘤的浸润。此外，全身免疫器官，如肿瘤引流淋巴结，脾,脾lipo-sunitinib治疗后，骨髓显示抗癌免疫力上调。
结论：我们的研究结果表明，lipo-sunitinib分布在RCC肿瘤部位，同时诱导有效的自噬，升高抗原呈递，激活细胞因子和趋化因子产生途径，并下调RCC细胞中的EMT。这种综合方法显着增强了肿瘤抑制作用并促进了抗癌免疫调节。
