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

Cancer Gene Therapy (2025)Cite this article

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Abstract

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.

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Fig. 1: The construction and transgene expression of two-armed oncolytic adenoviruses encoding GM-CSF.
Fig. 2: Effects of transgene insertion on cytotoxicity and apoptosis in a variety of cancer cell lines.
Fig. 3: The oAd-CMV-GM-CSF induced stronger autophagy.
Fig. 4: oAd-CMV-GM-CSF induces more profound autophagy through JAK2/STAT signaling pathway in cancer cell.
Fig. 5: oAd-CMV-GM-CSF promotes replication of oAd in cancer cell.
Fig. 6: oAd-CMV-GM-CSF augments propagation of the progeny viruses and induces ICD in A549 and PANC-1 cells.
Fig. 7: The oAd-CMV-GM-CSF has stronger anti-tumor effects in immunocompromised BALB/c-nu mice.
Fig. 8: The oAd-CMV-GM-CSF has stronger anti-tumor effects in immunocompetent Syrian hamster.

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Data availability

All relevant data supporting the findings of this study are included within the article or are available from the corresponding authors upon reasonable request. Further inquiries can be directed to the corresponding author, Fei Li, via email.

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (82272628, 22104040, and 81802608) and Knowledge Innovation Program of Wuhan-Shuguang Project (2023020201020496).

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  1. These authors contributed equally: Heng Cao, Jiaqi Ye.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    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

  2. National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    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

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Contributions

Conceptualization, W.XL., D.ZT. and L.F.; methodology, C.H., Y.JQ., L.XJ., S.Y., J.X., X.SF. and J.T.; validation, C.H., Y.JQ., W.XL., D.ZT. and L.F.; formal analysis, C.H., Y.JQ., D.ZT. and L.F.; investigation, D.Y., D.ZT. and L.F; resources, G.QL., M.D., W.XL. and L.F.; data curation, C.H., Y.JQ., D.ZT. and L.F.; writing-original draft preparation, L.F.; writing-review and editing, D.ZT.; supervision, M.D., W.XL. and L.F.; project administration, L.F. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Xiaoli Wang, Zhoutong Dai or Fei Li.

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All methods were performed in accordance with relevant guidelines and regulations. All animal experiments were approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (Approval No. 2023-3665) and conducted in the Specific Pathogen Free (SPF) animal facility at the Experimental Animal Center of Tongji Medical College. Female BALB/c nude mice and Syrian hamsters were procured from Beijing Vital River Laboratory Animal Technology Co., Ltd.

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Cao, H., Ye, J., Li, X. et al. A novel GM-CSF-encoding oncolytic adenovirus induces profound autophagy and promotes viral replication to enhance anti-tumor efficacy. Cancer Gene Ther (2025). https://doi.org/10.1038/s41417-025-00962-0

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