Orai1- and STIM1-mediated calcium signaling controls PD-L1 expression and modulates antitumor immunity in oral cancer

  • J Physiol Sci. 2026 Mar;76(1):100063. doi: 10.1016/j.jphyss.2026.100063.
Eriko Yamashita  1 ,  Soichiro Ishikawa  2 ,  Yuto Mizuno  3 ,  Yu Iida  4 ,  Mio Mochizuki  5 ,  Akane Nagasako  6 ,  Michiko Endo  7 ,  Kohei Osawa  8 ,  Yayoi Kimura  9 ,  Takayuki Fujita  10 ,  Utako Yokoyama  11 ,  Kenji Mitsudo  12 ,  Yoshihiro Ishikawa  13 ,  Masanari Umemura  14
Affiliations
  • 1. Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan; Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan. Electronic address: [email protected].
  • 2. Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan; Department of Clinical Oral Oncology, National hospital organization, Hokkaido Cancer Center, 3-54, 2-chome, Kikusui 4-jo, Shiroishi-ku, Sapporo-shi, Hokkaido 003-0804, Japan. Electronic address: [email protected].
  • 3. Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan. Electronic address: [email protected].
  • 4. Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan; Department of Neurosurgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan. Electronic address: [email protected].
  • 5. Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan. Electronic address: [email protected].
  • 6. Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan. Electronic address: [email protected].
  • 7. Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan. Electronic address: [email protected].
  • 8. Department of Oral and Maxillofacial Surgery/Orthodontics, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama-shi, Kanagawa 232-0024, Japan. Electronic address: [email protected].
  • 9. Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan. Electronic address: [email protected].
  • 10. Department of Physiology, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi, Fukuoka 814-0180, Japan. Electronic address: [email protected].
  • 11. Department of Physiology, Tokyo Medical University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Electronic address: [email protected].
  • 12. Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan. Electronic address: [email protected].
  • 13. Yokohama City University President, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan.
  • 14. Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan. Electronic address: [email protected].
PMID: 41666838 DOI: 10.1016/j.jphyss.2026.100063
Abstract

This study investigated the regulation of PD-L1 expression by calcium signaling in oral squamous cell carcinoma (OSCC). We found that IFN-γ stimulation markedly altered the intracellular proteome and activated calcium-associated pathways. Pharmacological inhibition of store-operated calcium entry (SOCE) using the Orai1 inhibitor Synta66 suppressed IFN-γ-induced PD-L1 expression in a dose-dependent manner. Consistently, knockdown of Orai1 or STIM1 attenuated PD-L1 induction under IFN-γ stimulation, while basal expression remained unchanged. Inhibition of CaMK2 and CaMKK2 also reduced PD-L1 expression, indicating involvement of calmodulin-dependent kinase pathways. Functionally, Orai1 or STIM1 knockdown enhanced CD8⁺ T cell-mediated suppression of OSCC cell proliferation. Collectively, these results demonstrate that SOCE-mediated calcium signaling and downstream kinases regulate IFN-γ-induced PD-L1 expression and suggest that targeting SOCE components could represent a novel therapeutic approach to overcoming tumor immune evasion in OSCC. (132 words).

Keywords
Interferon-gamma (IFN-γ); Oral squamous cell carcinoma (OSCC); PD-L1; Store-operated calcium entry (SOCE); Tumor immune evasion.
Products