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<p>Radiotherapy (RT) resistance is a major obstacle in breast cancer (BC) treatment. Although the role of tumor-derived exosomal (Exo) lncRNAs in RT resistance and macrophage M2 polarization has been recognized, the mechanism by which Exo LINC01943 regulates macrophage polarization to influence BC RT resistance remains unclear. This study aimed to investigate the molecular mechanism by which RT regulates macrophage M2 polarization through BC cell-derived Exo LINC01943. An orthotopic xenograft tumor model was established by injecting MDA-MB-231 cells into nude mice, and experiments were conducted by co-culturing BC cell-derived Exo (from MDA-MB-231) with M0 macrophages. Exo were characterized using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Macrophage polarization was assessed via RT-qPCR, flow cytometry, and ELISA. Autophagy was evaluated using immunofluorescence, Western blot, and MDC staining. The result shows that LINC01943 was highly expressed in BC and correlated with macrophage polarization. Further studies revealed that RT promoted the release of LINC01943 from MDA-MB-231-derived Exo. Under RT induction, Exo LINC01943 significantly upregulated M2 markers (CD206, IL-10, CD163, CCL22) and inflammatory factors (TGF-β1, IL-10) in macrophages, thereby promoting M2 polarization. Additionally, Exo LINC01943 increased p62 expression while reducing LC3-Ⅱ/Ⅰ and Beclin1 levels, suppressing autophagosome accumulation. Mechanistically, RT upregulated hnRNPA2B1 in MDA-MB-231 cells, stabilizing LINC01943 expression and facilitating its transfer to macrophages via Exo. In macrophages, overexpressed ELAVL1 promoted autophagy, and the autophagy activator Rapamycin reversed LINC01943-induced M2 polarization. Overall, this study found that RT upregulates hnRNPA2B1 to stabilize LINC01943 expression and enhance its Exo-mediated release, which subsequently inhibits ELAVL1-dependent autophagy in macrophages, accelerating M2 polarization.</p>

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Radiotherapy affects the ELAVL1-mediated autophagy pathway by promoting the release of LINC01943 exosomes in breast cancer cells to accelerate the M2 polarization of macrophages

  • 期刊论文

  • 发表日期：

    2025年11月24日

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  • Li Wang,
  • Han Bai,
  • Songqin Li,
  • Man Li,
  • Zaoxiu Hu,
  • Yaoxiong Xia

摘要

Radiotherapy (RT) resistance is a major obstacle in breast cancer (BC) treatment. Although the role of tumor-derived exosomal (Exo) lncRNAs in RT resistance and macrophage M2 polarization has been recognized, the mechanism by which Exo LINC01943 regulates macrophage polarization to influence BC RT resistance remains unclear. This study aimed to investigate the molecular mechanism by which RT regulates macrophage M2 polarization through BC cell-derived Exo LINC01943. An orthotopic xenograft tumor model was established by injecting MDA-MB-231 cells into nude mice, and experiments were conducted by co-culturing BC cell-derived Exo (from MDA-MB-231) with M0 macrophages. Exo were characterized using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Macrophage polarization was assessed via RT-qPCR, flow cytometry, and ELISA. Autophagy was evaluated using immunofluorescence, Western blot, and MDC staining. The result shows that LINC01943 was highly expressed in BC and correlated with macrophage polarization. Further studies revealed that RT promoted the release of LINC01943 from MDA-MB-231-derived Exo. Under RT induction, Exo LINC01943 significantly upregulated M2 markers (CD206, IL-10, CD163, CCL22) and inflammatory factors (TGF-β1, IL-10) in macrophages, thereby promoting M2 polarization. Additionally, Exo LINC01943 increased p62 expression while reducing LC3-Ⅱ/Ⅰ and Beclin1 levels, suppressing autophagosome accumulation. Mechanistically, RT upregulated hnRNPA2B1 in MDA-MB-231 cells, stabilizing LINC01943 expression and facilitating its transfer to macrophages via Exo. In macrophages, overexpressed ELAVL1 promoted autophagy, and the autophagy activator Rapamycin reversed LINC01943-induced M2 polarization. Overall, this study found that RT upregulates hnRNPA2B1 to stabilize LINC01943 expression and enhance its Exo-mediated release, which subsequently inhibits ELAVL1-dependent autophagy in macrophages, accelerating M2 polarization.