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Prevention of cancer initiation by augmenting MHC-I antigen presentation via EZH2 inhibition

Oncogene volume 44, pages 4878–4894 (2025)Cite this article

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Abstract

Early intervention of precancers is significant for improving cancer outcome. EZH2-mediated epigenetic modification was responsible for the immune escape of cancers; besides, tumor immune evasion is correlated with the impaired MHC-I antigen presentation machinery (APM). Oral potentially malignant disorders (OPMDs), represented by oral leukoplakia (OLK), usually precede head and neck squamous cell carcinoma (HNSCC). EZH2 is correlated with malignant transformation (MT) of OPMDs including OLK, while it remains undetermined that whether EZH2 mediates the initiation of HNSCC by repressing APM. Herein, EZH2 was first reported to negatively correlate with MHC-I and CD8+ GZMB+ T subsets which promote antitumor immunity in OPMDs. In vitro study uncovered that EZH2 triggers H3K27me3 on the promoters of MHC-I associated genes such as HLA-A/B/C, B2M and TAP1. Next, we constructed one hydrogel loaded with GSK126, a specific EZH2 inhibitor, denoted as PPT@GSK126 which is well-tolerated and highly adhesive to mucosa. Preclinical trials demonstrated that topical PPT@GSK126 could significantly prevent the MT of OPMDs and induce robust specific immune killing of dysplastic cells; while individual local αPD-1 therapy was unavailable, PPT@GSK126 synergized with topical αPD-1 therapy to significantly repress the cancerization of OPMDs. As EZH2 is highly expressed in numerous precancers, PPT@GSK126 has broad application prospects for reducing these tumor burdens.

Schematic images presenting the mechanism of action regarding EZH2 in promoting MT of OLK into HNSCC via inhibiting MHC-I associated APM (left panel) and the proposed therapeutic strategy for preventing OLK carcinogenesis (right panel).

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Fig. 1: The epithelium-originated EZH2 increases alongside with incremental severity of epithelial dysplasia of OLK.
Fig. 2: EZH2 is associated with the attenuated function of CD8+ T cells within microenvironment of OLK by histone epigenetic modulation.
Fig. 3: EZH2 inhibition or knockdown would not influence the growth potential of OLK but reduce the level of H3K27me3.
Fig. 4: EZH2 inhibition restores the MHC-I APM through transcriptionally upregulating relevant genes.
Fig. 5: PPT@GSK126 hydrogel is biosafe, highly adhesive, and suitable for local slow-releasing of EZH2 inhibitors.
Fig. 6: PPT@GSK126 hydrogel significantly retards the MT of OLK into HNSCC and enhances the efficacy of local immunotherapy.
Fig. 7: PPT@GSK126 hydrogel combined with local ICIs remarkably facilitates the MHC-I APM and triggers robust anti-tumor immunity.

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Data availability

The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2021) in National Genomics Data Center (Nucleic Acids Res 2024), China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA001006) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human.onco.

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Acknowledgements

We would like to appreciate all patients participating in this study.

Funding

This work is supported by: National Natural Science Foundation of China 82272899(to XL), 82203180 (to YQ), and 82171809 (to LJ). Research Funding from West China School/Hospital of Stomatology Sichuan University No. RCDWJS2022-16 (to XL). Key Research Program of Sichuan Provincial Science and Technology Agency 2023YFS0127 (to XL). Postdoctoral Research Funding of Sichuan University 2022SCU12132 (to XL). Research and Develop Program, West China Hospital of Stomatology, Sichuan University No. RD-02-202204 (to XL). Youth Fund Projects of Sichuan Provincial Science and Technology Agency 2024NSFSC1904(to YQ). The CAMS Innovation Fund for Medical Sciences CIFMS,2019-I2M-5-004 (to QC). Sichuan Science and Technology Program 2024YFFK0083(to LJ).

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Author notes

  1. These authors contributed equally: Wei Ding, Zihan Ding, Qinghong Zeng.

Authors and Affiliations

  1. State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China

    Wei Ding, Zihan Ding, Yuqi Wu, Yuchen Jiang, Qi Han, Hao Xu, Hao Cui, Xiangfei Liu, Xin Chen, Sixin Jiang, Mei Huang, Dan Pan, Dan Yang, Lihong Yao, Jing Li, Taiwen Li, Xiaoping Xu, Qianming Chen, Hang Zhao, Lu Jiang & Xiaobo Luo

  2. College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, China

    Qinghong Zeng & Longyu Li

  3. Department of Pathology, West China Hospital, Sichuan University, Chengdu, China

    Yan Qiu

  4. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, NC, USA

    Christopher R. Donnelly

  5. Institute of Clinical Pathology, West China Hospital of Sichuan University, Chengdu, China

    Li Li

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

    Minghai Tang

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  1. Wei Ding
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Contributions

WD, QZ, ZD contributed equally to this work. XL, LJ, and LL contributed equally to this work. Conceptualization: LJ, LL, XL. Methodology: WD, QZ, ZD, QH, HX, JL, CD, YQ. Investigation: WD, YQ, XL, XC, SJ, MH, DP, DY. Visualization: YW, HC, YQ, YJ. Supervision: LJ, LL, XL, LiL, LY, MT, TL, QC, XX. Writing—original draft: WD, QZ, ZD, YQ, XL. Writing—review and editing: XL, LJ, LL, CD.

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Correspondence to Longyu Li, Lu Jiang or Xiaobo Luo.

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All experimental procedures were conducted in accordance with the relevant institutional guidelines and regulations. A total of 27 biopsy specimens from patients diagnosed with oral leukoplakia (OLK) and OLK with malignant transformation at the West China Hospital of Stomatology, Sichuan University, were included in this study. Histopathological evaluation of all specimens was independently performed by two certified pathologists. The study protocol was reviewed and approved by the Institutional Review Board of the West China Hospital of Stomatology, Sichuan University (approval numbers: WCHSIRB-AT-2025-402 and WCHSIRB-D-2025-062). Written informed consent was obtained from all participants prior to their inclusion in the study.

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Ding, W., Ding, Z., Zeng, Q. et al. Prevention of cancer initiation by augmenting MHC-I antigen presentation via EZH2 inhibition. Oncogene 44, 4878–4894 (2025). https://doi.org/10.1038/s41388-025-03646-z

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