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Targeting the poliovirus receptor to activate T cells and induce myeloid-derived suppressor cells to differentiate to pro-inflammatory macrophages via the IFN-γ-p-STAT1-IRF8 axis in cancer therapy

Cell Death & Differentiation volume 32, pages 1791–1805 (2025)Cite this article

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Abstract

T cell immunoglobulin and ITIM domain (TIGIT) is one of the most important immune checkpoints expressed on lymphocytes, and poliovirus receptor (PVR, also CD155) serves as the most crucial ligand for TIGIT, harboring an important function in cancer cells and influencing the tumor microenvironment (TME). While it’s well-established that TIGIT blockade could reverse immunosuppression, the question of whether direct inhibition of PVR yields comparable results remains to be fully elucidated. This study investigated the role of PVR within the TME on the LLC, CT26 and MC38 tumor models and found that direct blockade of PVR on tumor cells could trigger T cell activation, enhance the production of immunostimulatory cytokine IFN-γ, and drive the differentiation of intratumoral myeloid-derived suppressor cells (MDSCs) into pro-inflammatory macrophages through the IFN-γ-p-STAT1-IRF8 axis. Furthermore, this study found that the anti-PVR nanobody monotherapy reduced tumor volume in the CT26 and MC38 tumor models. Combination of anti-PVR nanobody and anti-PD-1 antibody was effective in the LLC, CT26 and MC38 tumor models and had acceptable toxicity. These findings collectively suggest that PVR exhibits considerable promise as a therapeutic target in the development of immunotherapies aimed at augmenting the anti-tumor immune response.

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Fig. 1: Loss of Pvr slows tumor growth by reducing the frequency of MDSCs in TME.
Fig. 2: Loss of Pvr reduces the proportion of intra-tumoral M-MDSCs and increase central memory and effector CD8+ T cells.
Fig. 3: Loss of Pvr significantly elevates levels of intra-tumoral chemokines and creates an inflammatory TME.
Fig. 4: scRNA-seq identifies MDSCs and reveals the enhanced differentiation potential of M-MDSCs within the Pvr-KO TME.
Fig. 5: Pseudotime analysis reveals distinct M-MDSCs differentiation trajectory towards pro-inflammatory macrophages within the Pvr-KO TME.
Fig. 6: CD8+ Tpex and CD4+ Th1 cells significantly enriched and produced more IFN-γ within Pvr-KO TME.
Fig. 7: Activated T cells enhance the M-MDSCs differentiation via the IFN-γ-p-STAT1-IRF8 axis.

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Data availability

The data generated in this study are available within the article and its supplementary data files. Raw data are available upon request from the corresponding author.

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Funding

This work was supported by the National Natural Science Foundation of China (82073369 and 82303745), the Sichuan Science and Technology Program (2023YFS0003) and the Natural Science Foundation of Sichuan Province (2023NSFSC1855 and 2022NSFSC1564).

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Author notes

  1. These authors contributed equally: Mingyang Feng, Qizhi Ma, Benxia Zhang, Yue Chen.

Authors and Affiliations

  1. Department of Medical Oncology, Cancer Center, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

    Mingyang Feng, Qizhi Ma, Benxia Zhang, Yue Chen, Yang Yang, Xia He, Yao Zeng, Xuejin Ou, Weiting Liao, Xiaoyu Li, Sirui Tan, Diyuan Qin & Qiu Li

  2. Clinical Trial Center, West China Hospital, Sichuan University, Chengdu, China

    Benxia Zhang, Yue Chen, Xia He, Yixian Liu, Xiaoyu Li & Diyuan Qin

  3. National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital, Sichuan University, Chengdu, China

    Xia He

  4. Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, China

    Xia He

  5. Department of Pathology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China

    Meng Jing

  6. State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

    Qian Li

  7. Precision Medicine Center, West China Hospital, Sichuan University, Chengdu, China

    Dan Li

  8. Division of Thoracic Tumor Multimodality Treatment, Cancer Center, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

    Yongsheng Wang

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Contributions

MYF, SRT, DYQ, DL, QL, YSW contributed to the study conception and design. Material preparation, data collection and analysis were performed by MYF, QZM, BXZ, YC, YY, XH, YZ, MJ, XJO, YXL, QL, WTL and XYL. Bioinformatics analysis was mainly done by MYF. The drafts of the manuscript were written by MYF, QL and YSW. All authors read and approved the final manuscript.

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Correspondence to Qiu Li or Yongsheng Wang.

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Feng, M., Ma, Q., Zhang, B. et al. Targeting the poliovirus receptor to activate T cells and induce myeloid-derived suppressor cells to differentiate to pro-inflammatory macrophages via the IFN-γ-p-STAT1-IRF8 axis in cancer therapy. Cell Death Differ 32, 1791–1805 (2025). https://doi.org/10.1038/s41418-025-01496-6

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