{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:48:50Z","timestamp":1785408530713,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP23K24551 and JP22H03293"],"award-info":[{"award-number":["JP23K24551 and JP22H03293"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"award":["JP23K24551 and JP22H03293"],"award-info":[{"award-number":["JP23K24551 and JP22H03293"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy characterized by aggressive behavior and limited therapeutic options. Bitter taste receptors (TAS2Rs), expressed across multiple tissues and cancer types, have recently emerged as regulators of tumor biology and immune responses; however, their functional significance in OSCC remains poorly understood. Methods: Immunohistochemical analysis was performed using surgically resected human tongue OSCC specimens and a tissue microarray (TMA) cohort. In parallel, four TAS2R agonists were evaluated in SCC7 cells to assess intracellular calcium responses. RNA sequencing was conducted to analyze transcriptional changes following diphenidol treatment, and functional assays, including proliferation, migration, and apoptosis analyses, were performed in vitro. Antitumor effects were further evaluated in a syngeneic SCC7 mouse model, followed by TUNEL staining and flow cytometry to assess apoptosis and immune cell infiltration. Results: TAS2R38 expression was markedly upregulated in dysplastic and invasive OSCC lesions with predominant nuclear localization and was associated with histological grade and clinical stage, indicating an early and sustained alteration during tumor progression. Among the agonists tested, diphenidol most strongly induced IP3-dependent intracellular Ca2+ elevation. RNA sequencing revealed upregulation of Il1rl1 and Lzts2. Functionally, diphenidol significantly suppressed SCC7 cell proliferation and migration and induced apoptosis in vitro. In vivo, diphenidol reduced tumor volume and weight and increased apoptotic activity. Flow cytometry demonstrated a marked reduction in tumor-infiltrating CD4+CD25+Foxp3+ regulatory T cells, indicating modulation of the tumor immune microenvironment. Conclusions: TAS2R activation by diphenidol suppresses tumor growth through both tumor-intrinsic mechanisms and modulation of the tumor immune microenvironment in OSCC. These findings define TAS2R-mediated calcium signaling as a novel axis linking tumor progression and immunoregulation. Given that diphenidol is a clinically approved drug with an established safety profile, our results provide a strong rationale for TAS2R-targeted drug repurposing strategies in cancer therapy.<\/jats:p>","DOI":"10.3390\/cancers18101527","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:05:22Z","timestamp":1778501122000},"page":"1527","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activation of TAS2R Signaling by Diphenidol Suppresses Tumor Growth and Remodels the Tumor Immune Microenvironment in Oral Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Nisrina Ekayani","family":"Nasrun","sequence":"first","affiliation":[{"name":"Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu 061-0293, Japan"},{"name":"Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Hasanuddin University, Makassar 90245, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Tanimura","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koki","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu 061-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5602-4448","authenticated-orcid":false,"given":"Osamu","family":"Uehara","sequence":"additional","affiliation":[{"name":"Division of Disease Control and Molecular Epidemiology, Department of Oral Growth and Development, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu 061-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kunisada","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyofumi","family":"Takabatake","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Hosoya","sequence":"additional","affiliation":[{"name":"Division of Craniofacial Development and Tissue Biology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Takebe","sequence":"additional","affiliation":[{"name":"Division of Histology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu 061-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Nagatsuka","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Abiko","sequence":"additional","affiliation":[{"name":"Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu 061-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0943-4000","authenticated-orcid":false,"given":"Muhammad","family":"Ruslin","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Hasanuddin University, Makassar 90245, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7811-2366","authenticated-orcid":false,"given":"Tsuyoshi","family":"Shimo","sequence":"additional","affiliation":[{"name":"Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu 061-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41368-023-00249-w","article-title":"Oral squamous cell carcinomas: State of the field and emerging directions","volume":"15","author":"Tan","year":"2023","journal-title":"Int. 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