{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T07:05:33Z","timestamp":1783926333532,"version":"3.55.0"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are associated with increased atherosclerotic cardiovascular disease (ASCVD) risk independent of plasma cholesterol levels. While T-cell activation after ICI treatment contributes to this risk, emerging data implicate vascular smooth muscle cells (SMCs) as contributors to increased ASCVD associated with ICIs. Here, we investigated the effect of the ICI nivolumab, a monoclonal antibody targeting programmed death 1 (PD-1), on cultured human SMCs and determined that it induced activation of heat shock factor 1 (HSF1), the principal transcriptional regulator of cytosolic stress. HSF1 activation led to increased activation of HMG-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis, and accumulation of cholesteryl esters. Nivolumab treatment also activated endoplasmic reticulum (ER) stress, particularly PERK signaling, and atherosclerosis-associated phenotypic modulation of SMCs. Nivolumab-induced cholesterol synthesis, PERK signaling, and SMC phenotypic modulation were reversed by neutralization and knockdown of PD-1, as well as treatment with the HMGCR inhibitor pravastatin. These results reveal that nivolumab induces HSF1-HMGCR-PERK signaling and SMC phenotypic modulation and provides a rationale for statin therapy to mitigate ICI-induced ASCVD even in normocholesterolemic patients, highlighting a potential strategy to prevent ASCVD in cancer survivors receiving ICIs.<\/jats:p>","DOI":"10.3389\/fcvm.2026.1789821","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T06:13:36Z","timestamp":1783923216000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune checkpoint inhibitor-driven smooth muscle cell phenotypic modulation: a potential contributor to atherosclerotic risk associated with these therapies"],"prefix":"10.3389","volume":"13","author":[{"given":"Abhijnan","family":"Chattopadhyay","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, The University of Texas Health 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Houston","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Panchal","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Callie S.","family":"Kwartler","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianna M.","family":"Milewicz","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at 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