理由：M2 样肿瘤相关巨噬细胞 (TAM) 促进胶质母细胞瘤的恶性进展。然而，造成这种现象的机制仍不清楚。方法：采用RT-PCR、Western blot和流式细胞术评估巨噬细胞的极化状态。 RT-PCR、蛋白质印迹或/和免疫组织化学用于测定circ_0003137、PTBP1、PLOD3和上皮间质转化（EMT）标志物的表达。 Transwell实验用于评估肿瘤细胞的迁移和侵袭能力。通过RNA测序、生物信息学分析和Pearson相关系数来探讨PTBP1和circ_003137/PLOD3之间的关系。使用体内实验来确定装载sh-circ_0003137的纳米平台的作用。结果：缺氧以 HIF1α 依赖性方式促进巨噬细胞向 M2 样 TAM 极化。然后，M2 样 TAM 可以将 circ_0003137 富集的细胞外囊泡 (EV) 转运至胶质母细胞瘤细胞，从而上调胶质母细胞瘤细胞中的 circ_0003137。 circ_0003137过表达促进体外和体内胶质母细胞瘤细胞的EMT。从机制上讲，circ_0003137 与聚嘧啶束结合蛋白 1 (PTBP1) 物理结合，增强前胶原赖氨酸、2-酮戊二酸 5-双加氧酶 3 (PLOD3) 的稳定性并促进胶质母细胞瘤细胞的 EMT。此外，还建立了一种基于脂质体的shRNA纳米平台，并用于封装sh-circ_0003137。荧光显微镜示踪和细胞共培养实验表明，sh-circ_0003137封装的纳米平台稳定，可以穿透血脑屏障（BBB），最终到达中枢神经系统（CNS）。颅内原位肿瘤模型显示，通过尾静脉注射负载sh-circ_0003137的纳米平台可显着抑制胶质母细胞瘤的进展并提高裸鼠的存活率。结论：缺氧可以驱动巨噬细胞向 M2 样 TAM 极化。极化的 M2 样 TAM 可以通过 EV 将 circ_0003137 转运至胶质母细胞瘤细胞。然后，circ_0003137通过靶向PTBP1/PLOD3轴促进胶质母细胞瘤的EMT。因此，针对 circ_0003137 可能是一种针对胶质母细胞瘤的新型治疗策略。© 作者。

Rationale: M2-like tumor-associated macrophages (TAMs) promote the malignant progression of glioblastomas. However, the mechanisms responsible for this phenomenon remain unclear. Methods: RT-PCR, Western blot and flow cytometry were used to evaluate the polarization status of macrophages. RT-PCR, western blot or/and immunohistochemistry was used to determine the expression of circ_0003137, PTBP1, PLOD3 and epithelial-mesenchymal transition (EMT) markers. Transwell assay was used to assess migration and invasion ability of tumor cells. RNA sequencing, bioinformatic analysis and Pearson correlation coefficient was performed to explore the relation between PTBP1 and circ_003137/PLOD3. In vivo experiment was used to determine the role of sh-circ_0003137-loaded nanoplatform. Results: Hypoxia promoted the polarization of macrophages towards M2-like TAMs in an HIF1α dependent manner. Then, M2-like TAMs could transport circ_0003137 enriched extracellular vesicles (EVs) to glioblastoma cells, upregulating circ_0003137 in glioblastoma cells. The circ_0003137 overexpression promoted the EMT of glioblastoma cells in vitro and in vivo. Mechanistically, circ_0003137 physically binds to polypyrimidine tract binding protein 1 (PTBP1), enhancing the stability of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) and promoting the EMT of glioblastoma cells. Moreover, a liposome-based nanoplatform that delivers shRNAs was established and used to encapsulate sh-circ_0003137. The fluorescence microscope tracer and cell co-culture assays demonstrated that the nanoplatform encapsulated with sh-circ_0003137 was stable and could penetrate the blood-brain barrier (BBB), finally reaching the central nervous system (CNS). The intracranial in situ tumor model showed that injecting the sh-circ_0003137-loaded nanoplatform via the tail vein significantly inhibited glioblastoma progression and improved the nude mice's survival. Conclusions: Hypoxia can drive macrophage polarization towards M2-like TAMs. Polarized M2-like TAMs can transport circ_0003137 to glioblastoma cells through EVs. Then, circ_0003137 promotes the EMT of glioblastomas by targeting the PTBP1/PLOD3 axis. Hence, targeting circ_0003137 might be a novel therapeutic strategy against glioblastoma.© The author(s).