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<p>Radiotherapy (RT) efficacy is limited by RT-induced immune resistance. Here we show that RT upregulates programmed death ligand 1 (PD-L1) on senescent tumor cells (STCs) via bromodomain-containing protein 4 (BRD4) signaling, thereby promoting immune evasion. To counter this, we develop POLY-Senolytic, a polymeric senolytic nanoparticle formed by conjugating an acid-responsive polymer to a peptide-based BRD4 PROteolysis-TArgeting Chimera via a reduction-cleavable disulfide bond. The POLY-Senolytic is activated in the acidic and reductive intracellular environment of tumor cells, leading to BRD4 degradation, suppression of RT-induced PD-L1 expression and enhanced immune clearance of STCs. Combined with RT, the POLY-Senolytic suppresses tumor growth and metastasis in orthotopic mouse models of pancreatic and breast tumors. We further engineer a β-galactosidase-responsive POLY-Tracker for real-time monitoring of senolytic therapy. Together, this study identifies an RT-driven BRD4-PD-L1 axis in STCs that promotes immune resistance and provides a practical strategy to eliminate and track them.</p>

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POLY-Senolytic nanoplatform for tumor-specific eradication of senescent tumor cells and mitigation of radiotherapy-induced immune resistance of cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月18日

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  • Yi Lai,
  • Shunan Zhang,
  • Jiaxing Pan,
  • Wenyue Lan,
  • Min Li,
  • Zifan Zhu,
  • Leiming Xu,
  • Bruno G. De Geest,
  • Twan Lammers,
  • Wen Zhang,
  • Haijun Yu,
  • Zhiai Xu

摘要

Radiotherapy (RT) efficacy is limited by RT-induced immune resistance. Here we show that RT upregulates programmed death ligand 1 (PD-L1) on senescent tumor cells (STCs) via bromodomain-containing protein 4 (BRD4) signaling, thereby promoting immune evasion. To counter this, we develop POLY-Senolytic, a polymeric senolytic nanoparticle formed by conjugating an acid-responsive polymer to a peptide-based BRD4 PROteolysis-TArgeting Chimera via a reduction-cleavable disulfide bond. The POLY-Senolytic is activated in the acidic and reductive intracellular environment of tumor cells, leading to BRD4 degradation, suppression of RT-induced PD-L1 expression and enhanced immune clearance of STCs. Combined with RT, the POLY-Senolytic suppresses tumor growth and metastasis in orthotopic mouse models of pancreatic and breast tumors. We further engineer a β-galactosidase-responsive POLY-Tracker for real-time monitoring of senolytic therapy. Together, this study identifies an RT-driven BRD4-PD-L1 axis in STCs that promotes immune resistance and provides a practical strategy to eliminate and track them.