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Background <p>Immunotherapy targeting the PD-1/PD-L1 axis shows promise in colon and lung cancer treatment but faces challenges like high costs, low response rates, and drug resistance. Developing new small molecule inhibitors is complex. Repurposing existing drugs offers advantages, and paroxetine (PAR), an FDA approved antidepressant, has shown potential antitumor effects, yet its role as an immune checkpoint inhibitor is unclear.</p> Methods <p>In this study, we investigated PAR as an immune checkpoint inhibitor. We used various cell lines, including colon and lung cancer cells, and in vivo mouse models. Techniques such as Western blotting, flow cytometry, immunofluorescence, and immunohistochemistry were employed to analyze protein expression, cell surface marker levels, and immune cell populations. We also conducted gene knockdown and overexpression experiments, as well as molecular docking and binding assays.</p> Results <p>PAR downregulates PD-L1 protein levels in a concentration and time dependent manner in multiple cancer cell lines. In vivo, it inhibits tumor growth in colon and lung cancer mouse models by activating T cell immunity. Mechanistically, PAR binds to the Asp130 site of speckle-type POZ protein (SPOP), stabilizing this E3 ubiquitin ligase to promote PD-L1 ubiquitination and proteasomal degradation. Moreover, PAR combines with an anti-CTLA4 antibody enhances cancer cell inhibition, and it also suppresses AOM/DSS induced colon cancer.</p> Conclusions <p>Our findings demonstrate that PAR can function as an immune checkpoint inhibitor by targeting SPOP to degrade PD-L1, enhancing antitumor immunity. This provides a new theoretical basis for using PAR in colorectal and lung cancer treatment and offers insights into repurposing other drugs for cancer therapy.</p> Graphical Abstract <p></p>

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Paroxetine repurposing enhances antitumor immunity via SPOP-mediated PD-L1 ubiquitination and proteasomal degradation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月27日

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  • Mengting Xu,
  • Saisai Tian,
  • Hanchi Xu,
  • Xinying Xue,
  • Qing Zhang,
  • Hongmei Hu,
  • Gaosong Wu,
  • Xiangxin Geng,
  • Dianping Yu,
  • Hanchen Xu,
  • Mei Xie,
  • Linyang Li,
  • Xinru Li,
  • Simeng Li,
  • Shize Xie,
  • Xuwen Lin,
  • Shuzhen Lyu,
  • Yutong Xie,
  • Biao Zhang,
  • Haiyang Zhou,
  • Qun Wang,
  • Weidong Zhang,
  • Sanhong Liu

摘要

Background

Immunotherapy targeting the PD-1/PD-L1 axis shows promise in colon and lung cancer treatment but faces challenges like high costs, low response rates, and drug resistance. Developing new small molecule inhibitors is complex. Repurposing existing drugs offers advantages, and paroxetine (PAR), an FDA approved antidepressant, has shown potential antitumor effects, yet its role as an immune checkpoint inhibitor is unclear.

Methods

In this study, we investigated PAR as an immune checkpoint inhibitor. We used various cell lines, including colon and lung cancer cells, and in vivo mouse models. Techniques such as Western blotting, flow cytometry, immunofluorescence, and immunohistochemistry were employed to analyze protein expression, cell surface marker levels, and immune cell populations. We also conducted gene knockdown and overexpression experiments, as well as molecular docking and binding assays.

Results

PAR downregulates PD-L1 protein levels in a concentration and time dependent manner in multiple cancer cell lines. In vivo, it inhibits tumor growth in colon and lung cancer mouse models by activating T cell immunity. Mechanistically, PAR binds to the Asp130 site of speckle-type POZ protein (SPOP), stabilizing this E3 ubiquitin ligase to promote PD-L1 ubiquitination and proteasomal degradation. Moreover, PAR combines with an anti-CTLA4 antibody enhances cancer cell inhibition, and it also suppresses AOM/DSS induced colon cancer.

Conclusions

Our findings demonstrate that PAR can function as an immune checkpoint inhibitor by targeting SPOP to degrade PD-L1, enhancing antitumor immunity. This provides a new theoretical basis for using PAR in colorectal and lung cancer treatment and offers insights into repurposing other drugs for cancer therapy.

Graphical Abstract