2. Academic Validation
  3. Targeting Intratumoral Copper Inhibits Tumor Progression via p62-Mediated EZH2 Degradation and Potentiates Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinoma

Targeting Intratumoral Copper Inhibits Tumor Progression via p62-Mediated EZH2 Degradation and Potentiates Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinoma

  • Adv Sci (Weinh). 2025 Jul 28:e17795. doi: 10.1002/advs.202417795.
Xiaohu Lin 1 2 3,  Wanling Chen 2 3 4,  Bo Li 5,  Zhang Zhao 1 2 3,  Zhonglin Yu 1 2 3,  Xu-Yun Zhao 6,  Xuan Zhou 7 8,  Zhien Feng 5,  Chengzhong Lin 9,  Wei Cao 1 2 3
Affiliations

Affiliations

  • 1 Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China.
  • 2 National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, 200011, China.
  • 3 Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
  • 4 Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China.
  • 5 Department of Oral and Maxillofacial-Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100070, China.
  • 6 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 7 Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, 300060, China.
  • 8 State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China.
  • 9 Department of Oral and Maxillofacial Surgery, Zhongshan Hospital Fudan University, No.180, Xietu Rd, Shanghai, 200011, China.
PMID: 40719074 DOI: 10.1002/advs.202417795
Abstract

High copper levels are required for tumor initiation and progression, termed cuproplasia. However, its role and underlying mechanisms in oral squamous cell carcinoma (OSCC) remain poorly understood. It is find that copper and its transporter SLC31A1 accumulate extensively in OSCC. Blocking copper influx through SLC31A1 siRNA or copper chelators significantly represses OSCC both in vitro and in vivo. Single-cell RNA Sequencing and multiplex immunohistochemical staining revealed that copper chelators specifically decrease the stem-like tumor epithelial cell subpopulation. Further investigation shows that intratumoral copper depletion reduces Histone Methyltransferase EZH2 expression at the protein level, but not at the mRNA level, as determined through a screen analysis of histone-modification Enzymes. Mechanistically, it is discovered that silencing SLC31A1 and treating with copper chelators increase p62-mediated EZH2 ubiquitination at the Ub-K63 site by suppressing copper binding to SMURF2, an E3 Ligase of EZH2, leading to its autophagic degradation. Additionally, combining copper chelators with anti-PD-1 treatment effectively suppresses tumor growth, and high levels of SLC31A1 are notably associated with non-response to anti-PD-1 treatment. In conclusion, the crucial role of copper in modulating EZH2 protein stability is demonstrated, and a new approach using copper chelators and anti-PD-1 therapy for OSCC patients is provided.

Keywords

EZH2; Immunotherapy; Intratumoral copper; OSCC; p62.

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