{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T06:47:58Z","timestamp":1782110878112,"version":"3.54.5"},"reference-count":36,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Diabetes mellitus (DM) is increasingly recognized for its role in modifying the tumor microenvironment, but its influence on immune checkpoints in cancer remains underexplored. This study investigates how diabetes\u2010associated conditions influence CD155 expression and immune evasion in ovarian cancer using murine preclinical models. Utilizing the murine ID8 ovarian cancer cell line and NOD mice, a widely used model of non\u2010obese diabetes, we assessed the impact of diabetes\u2010associated conditions on CD155 expression and immune cell infiltration. Our methodologies included overexpression and knockdown studies, Western blotting, PCR, flow cytometry, and tumor growth assays in murine models. We found that diabetes\u2010associated conditions enhanced HSP70 levels in ovarian cancer cells, facilitating P65 activation and subsequent upregulation of CD155. Elevated CD155 expression correlated with reduced efficacy of immune checkpoint blockade, decreased CD8 T\u2010cell infiltration, and impaired T\u2010cell activation and proliferation in the tumor microenvironment. Notably, diabetes\u2010associated conditions did not affect cancer cell stemness markers (CD44, CD271, GPR49) or regulatory T\u2010cell (Treg) infiltration, indicating that the immune modulation was specifically mediated through the HSP70\/P65\u2010CD155 pathway. In vivo, knockdown of HSP70 in diabetic murine tumor models reversed the upregulation of CD155, restoring immune surveillance and reducing tumor growth. These findings identify a diabetes\u2010associated HSP70\/P65\u2013CD155 signaling axis that promotes immune evasion in murine models of ovarian cancer. This study provides preclinical, hypothesis\u2010generating evidence for the role of metabolic stress in modulating tumor immune escape mechanisms, without implying direct clinical applicability. This research elucidates how diabetes mellitus exacerbates immune suppression in ovarian cancer by upregulating CD155 through the HSP70\/P65 axis, contributing to diminished cytotoxic T\u2010cell activity and increased resistance to immune checkpoint blockade (ICB) therapies. These findings emphasize the critical interplay between metabolic disorders and tumor immunology, suggesting potential therapeutic targets to enhance the efficacy of immunotherapy in diabetic cancer patients.<\/jats:p>","DOI":"10.1002\/jbt.70901","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T08:50:59Z","timestamp":1779094259000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diabetes Mellitus Enhances Immune Suppression in Ovarian Cancer via CD155 Upregulation Mediated by the HSP70\/P65 Axis"],"prefix":"10.1002","volume":"40","author":[{"given":"Lan","family":"Han","sequence":"first","affiliation":[{"name":"Gynecology Department Shenzhen Longhua Maternal and Child Health Hospital Shenzhen Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Zhang","sequence":"additional","affiliation":[{"name":"Gynecology Department Shenzhen Longhua Maternal and Child Health Hospital Shenzhen Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Qianhai Life Shaoguan Hospital Shaoguan Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanhang","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, the First Affiliated Hospital Sun Yat\u2010sen University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueru","family":"Li","sequence":"additional","affiliation":[{"name":"Gynecology Department The Third Affiliated Hospital of Shenzhen University Shenzhen Guangdong 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