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<p>Granulocyte-macrophage colony-stimulating factor (GM-CSF) acts as a double-edged sword in cancer by enhancing both anti- and pro-tumorigenic immune cells. In this study, two oncolytic adenoviruses were engineered to modulate GM-CSF expression using different strategies: one with the CMV promoter (oAd-CMV-GM-CSF) and the other using the endogenous viral E3 promoter (oAd-GM-CSF). The impacts of these modifications on transgene expression, cytotoxicity, viral replication, and apoptosis were assessed both in vitro and in vivo. The results demonstrated that oAd-CMV-GM-CSF produced significantly lower GM-CSF levels than oAd-GM-CSF, interestingly oAd-CMV-GM-CSF exhibited increased cytotoxicity and apoptosis compared to oAd-GM-CSF and control groups. The further study showed oAd-CMV-GM-CSF induced profound autophagy through the activation of the Janus kinase 2/Signal Transducer and Activator of Transcription 2 (JAK2/STAT2) signaling pathway. The use of autophagy and JAK-2 inhibitors, Chloroquine (CQ) and AG-490, respectively, significantly mitigated the apoptosis induced by oAd-CMV-GM-CSF. In addition, oAd-CMV-GM-CSF presented a faster viral replication and production of more active progeny virus than oAd-GM-CSF, which could be inhibited by CQ. oAd-CMV-GM-CSF augments propagation of the progeny viruses and induces immunogenic cell death(ICD) in A549 and PANC-1 cells. In vivo oAd-CMV-GM-CSF had stronger anti-tumor effect than oAd-GM-CSF in immunodeficient model and immune-competent model. Our findings indicate that oAd-CMV-GM-CSF induces more profound autophagy and promoting viral replication to enhance the anti-tumor efficacy.</p>

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A novel GM-CSF-encoding oncolytic adenovirus induces profound autophagy and promotes viral replication to enhance anti-tumor efficacy

  • 期刊论文

  • 发表日期：

    2025年9月17日

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  • Heng Cao,
  • Jiaqi Ye,
  • Xiaojiao Li,
  • Yao Si,
  • Xin Jin,
  • Shengfeng Xiong,
  • Teng Ji,
  • Yi Ding,
  • Ding Ma,
  • Qinglei Gao,
  • Xiaoli Wang,
  • Zhoutong Dai,
  • Fei Li

摘要

Granulocyte-macrophage colony-stimulating factor (GM-CSF) acts as a double-edged sword in cancer by enhancing both anti- and pro-tumorigenic immune cells. In this study, two oncolytic adenoviruses were engineered to modulate GM-CSF expression using different strategies: one with the CMV promoter (oAd-CMV-GM-CSF) and the other using the endogenous viral E3 promoter (oAd-GM-CSF). The impacts of these modifications on transgene expression, cytotoxicity, viral replication, and apoptosis were assessed both in vitro and in vivo. The results demonstrated that oAd-CMV-GM-CSF produced significantly lower GM-CSF levels than oAd-GM-CSF, interestingly oAd-CMV-GM-CSF exhibited increased cytotoxicity and apoptosis compared to oAd-GM-CSF and control groups. The further study showed oAd-CMV-GM-CSF induced profound autophagy through the activation of the Janus kinase 2/Signal Transducer and Activator of Transcription 2 (JAK2/STAT2) signaling pathway. The use of autophagy and JAK-2 inhibitors, Chloroquine (CQ) and AG-490, respectively, significantly mitigated the apoptosis induced by oAd-CMV-GM-CSF. In addition, oAd-CMV-GM-CSF presented a faster viral replication and production of more active progeny virus than oAd-GM-CSF, which could be inhibited by CQ. oAd-CMV-GM-CSF augments propagation of the progeny viruses and induces immunogenic cell death(ICD) in A549 and PANC-1 cells. In vivo oAd-CMV-GM-CSF had stronger anti-tumor effect than oAd-GM-CSF in immunodeficient model and immune-competent model. Our findings indicate that oAd-CMV-GM-CSF induces more profound autophagy and promoting viral replication to enhance the anti-tumor efficacy.