2. Academic Validation
  3. Hyaluronic acid-CD44 signaling defines therapeutic resistance and immunosuppressive microenvironment in peritoneal metastasis of gastric cancer

Hyaluronic acid-CD44 signaling defines therapeutic resistance and immunosuppressive microenvironment in peritoneal metastasis of gastric cancer

  • J Immunother Cancer. 2026 Mar 9;14(3):e014179. doi: 10.1136/jitc-2025-014179.
Junjie Zhao # 1 2,  Chengbo Ji # 1 2,  Jie Sun # 1 2,  Chenyu Tian 1 2,  Tianyi Cai 1 2,  Zhaoming Wang 1 2,  Zhaodong Sun 1 2,  Bosen Li 3,  Guoxing Ma 1 2,  Dan Liu 1 2,  Masami Yamamoto 4,  Tetsuya Tsukamoto 5,  Sachiyo Nomura 6,  Liming Sun 7,  Yihong Sun 1 2 3,  Liyu Huang 8 9,  Yuanyuan Ruan 10 11,  Haojie Li 10 2 3,  Xuefei Wang 10 2 3 12
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 Gastric Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 Department of General Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China.
  • 4 Laboratory of Physiological Pathology, Nippon Veterinary and Life Science University, Musashino, Tokyo, Japan.
  • 5 Department of Diagnostic Pathology, Fujita Health University School of Medicine Graduate School of Medicine, Toyoake, Aichi, Japan.
  • 6 Department of Clinical Pharmaceutical Sciences, School of Pharmacy and 19 Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
  • 7 Shanghai Clinical Research and Trial Center, ShanghaiTech University, Shanghai, China.
  • 8 Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China [email protected] [email protected] [email protected] [email protected].
  • 9 Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, China.
  • 10 Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China [email protected] [email protected] [email protected] [email protected].
  • 11 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 12 Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, China.
  • # Contributed equally.
PMID: 41802813 DOI: 10.1136/jitc-2025-014179
Abstract

Background: Peritoneal metastasis (PM) is one of the most challenging clinical problems in gastric Cancer (GC), largely due to its high recurrence rate and poor response to current therapies. Increasing evidence indicates that remodeling of the extracellular matrix (ECM) plays an important role in therapeutic failure. However, how specific stromal-immune interactions contribute to PM heterogeneity and immunotherapy resistance remains unclear. In this study, we investigated how ECM composition-particularly the accumulation of hyaluronic acid (HA)-influences the immune microenvironment and therapeutic responses in GC-associated PM.

Methods: We combined histopathological assessment, analyses of patient-derived specimens, single-cell transcriptomic profiling, and murine models of PM to delineate ECM remodeling patterns and immune cell dynamics in therapy-sensitive and therapy-resistant lesions. In addition, functional assays and pharmacological approaches were used to examine HA-CD44 signaling and its impact on CD4+ T cell differentiation and responsiveness to immune checkpoint blockade.

Results: Therapy-sensitive PM lesions were characterized by enrichment of elastic fibers, whereas therapy-resistant lesions showed Collagen accumulation. Notably, HA deposition emerged as a key feature distinguishing these ECM states and was closely associated with differential therapeutic outcomes. Elevated HA levels activated CD44-dependent signaling in CD4+ T cells, driving regulatory T cell (Treg) differentiation through a CD44-IQGAP1-RAC1-SMAD3 signaling pathway and thereby establishing an immunosuppressive microenvironment. Importantly, pharmacological inhibition of CD44 reduced Treg expansion and markedly enhanced the antitumor efficacy of anti-PD-1 therapy in murine PM models.

Conclusions: Our findings identify HA-CD44 signaling as a critical link between ECM remodeling and immune evasion in GC PM. Targeting ECM-driven immunosuppressive mechanisms may represent a promising strategy to overcome therapeutic resistance and improve the efficacy of immunotherapy in this aggressive disease.

Keywords

Gastric Cancer; Tumor Microenvironment.

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