Tissue-specific inflammation induces cell state plasticity with oncogenic addiction in mucosal melanoma

  • Sci Adv. 2026 Apr 3;12(14):eady4536. doi: 10.1126/sciadv.ady4536.
Xuhui Ma  1  2  3 ,  Yanni Ma  4  5 ,  Li Zhang  5  6 ,  Ruixin Liu  4  5 ,  Ronghui Xia  7 ,  Meiling Hao  5 ,  Xiaole Song  8  9 ,  Yinan Chen  5 ,  Yang Zheng  1  2  3 ,  Hao Wang  5 ,  Hao Luo  5 ,  Shengnan Zheng  5 ,  Jie Yang  5 ,  Qin Yang  5 ,  Ruixin Jiang  4  5 ,  Xiangyu Chen  5  10 ,  Pengcong Hou  4  5 ,  Kaiyuan Hui  11 ,  Qian Bian  5 ,  Bin Jiang  4  5 ,  Xiaodong Jiang  11 ,  Min Jiang  12 ,  Yanjie Zhang  4  5 ,  A Hunter Shain  13  14 ,  Guoxin Ren  1  2  3 ,  Ming Lei  5 ,  Robert L Judson-Torres  15  16 ,  Wei Guo  1  2  3 ,  Hanlin Zeng  4  5
Affiliations
  • 1. Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 2. College of Stomatology, Shanghai Jiao Tong University, Shanghai 200025, China.
  • 3. Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai 200011, China.
  • 4. Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 5. Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 6. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 7. Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 8. Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China.
  • 9. Mucosal Melanoma Diagnosis and Treatment Center, Eye & ENT Hospital, Fudan University, Shanghai 200031, China.
  • 10. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 11. Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Jiangsu 222061, China.
  • 12. Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
  • 13. Department of Dermatology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 14. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 15. Department of Dermatology, University of Utah Salt Lake City, UT 84112, USA.
  • 16. Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
PMID: 41920996 DOI: 10.1126/sciadv.ady4536
Abstract

Mucosal melanoma (MM), an aggressive melanoma subtype arising in mucosal tissues, displays resistance to therapies effective in cutaneous melanoma. To understand how mucosal microenvironment contributes to treatment nonresponsiveness, we performed integrative analysis of single-cell and bulk messenger RNA Sequencing data derived from oral mucosa-originated melanoma and revealed that mucosa-specific inflammation induces enrichment of low-pigmented neural crest-like Cancer cell, mediated by COX2+ macrophages and their secretome. Maintenance of this inflammation-induced neural crest-like state in Cancer cells depends on HER2 and HER3 activation. Inhibition of HER2/3 by pan-HER inhibitors blocks cell state plasticity and overcomes chemoresistance in primary MM cell lines and patient-derived xenograft (PDX) models. These findings provide insights into how the tissue of origin determines Cancer aggressiveness, highlight the role of mucosal inflammation in driving melanoma stemness and chemoresistance, and advance the identification of effective treatment options currently lacking for patients with MM.

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