{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:42:47Z","timestamp":1788914567960,"version":"build-2803163510"},"reference-count":84,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA245081"],"award-info":[{"award-number":["R01CA245081"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body\u2019s surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL. We found that CTCL cells were &gt;5-fold more sensitive to the proteasome inhibitor bortezomib (Btz) and exhibited a distinct signaling and transcriptional response compared to normal CD4+ cells. The CTCL response was dominated by the induction of the HSP70 family member HSPA6 (HSP70B\u2019) and, to a lesser extent, HSPA5 (BiP\/GRP78). To understand the significance of these two factors, we used a novel isoform selective small-molecule inhibitor of HSPA5\/6 (JG-023). JG-023 induced pro-apoptotic UPR signaling and enhanced the cytotoxic effects of proteasome inhibitors and other UPR-inducing drugs in CTCL but not normal T cells. Interestingly, JG-023 also selectively suppressed the production of Th2 cytokines in CTCL and normal CD4+ T cells. Conditioned media (CM) from CTCL were immunosuppressive to normal T cells through an IL-10-dependent mechanism. This immunosuppression could be reversed by JG-023, other HSP70 inhibitors, Btz, and combinations of these UPR-targeted drugs. Our study points to the importance of the UPR in the pathology of CTCL and demonstrates the potential of proteasome and targeted HSPA5\/6 inhibitors for therapy.<\/jats:p>","DOI":"10.3390\/biom15010076","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T05:06:34Z","timestamp":1736226394000},"page":"76","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-4491","authenticated-orcid":false,"given":"Nadia","family":"St. Thomas","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin N.","family":"Christopher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Reyes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reeder M.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0669-8190","authenticated-orcid":false,"given":"Lena","family":"Golick","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2049-9561","authenticated-orcid":false,"given":"Xiaoyi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Center for Inflammation Science and Systems Medicine, University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6310-1664","authenticated-orcid":false,"given":"Eli","family":"Chapman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Center for Inflammation Science and Systems Medicine, University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan G.","family":"Dolloff","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA"},{"name":"Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Zucker Institute for Innovation Commercialization, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1182\/blood-2007-03-055749","article-title":"Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: A proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC)","volume":"110","author":"Olsen","year":"2007","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.21037\/cco.2019.01.02","article-title":"Systemic therapy of cutaneous T-cell lymphoma (CTCL)","volume":"8","author":"Alpdogan","year":"2019","journal-title":"Chin. 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