Nab-Paclitaxel Promotes Radiosensitization by Inducing DNA Damage and Inhibiting Macrophage M2 Polarization in...

Nab-paclitaxel effectively inhibits tumor proliferation and modulates macrophage polarization to improve the tumor microenvironment. However, its potential to achieve radiosensitization in cholangiocarcinoma remains to be elucidated. The proliferation inhibition and radiosensitizing effects of nab-paclitaxel were assessed using cell counting kit-8 and colony formation assays in NOZ and TFK1 cell lines. Cell apoptosis, cell cycle progression, DNA damage, and macrophage polarization status were analyzed via flow cytometry immunofluorescence, enzyme-linked immunosorbent assay, and qRT-PCR. A tumor-bearing mouse model was established to validate radiosensitization in vivo. Potentially related genes and proteins involved in nab-paclitaxel-induced radiosensitization were identified through RNA transcriptome sequencing and Western blotting. Nab-paclitaxel exhibited significant radiosensitizing effects on cholangiocarcinoma cells. Combined with radiotherapy, nab-paclitaxel increased DNA damage, promoted apoptosis, and effectively inhibited M2 polarization of macrophages in vivo and in vitro. The radiosensitizing effect is involved in the activation of the AMP-dependent protein kinase (AMPK) signaling pathway. Nab-paclitaxel significantly upregulated phosphorylated AMPKα, apoptotic proteins as zinc finger matrin-type 3, and nuclear factor kappa-B levels following radiation exposure. Our study confirmed the radiosensitizing effect of nab-paclitaxel on cholangiocarcinoma cells through a dual effect of antitumor proliferation and inhibition of M2 macrophage polarization, and the underlying mechanism involved activation of the AMPK signaling pathway.