{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T18:14:36Z","timestamp":1764785676401,"version":"build-2065373602"},"reference-count":68,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,14]],"date-time":"2025-09-14T00:00:00Z","timestamp":1757808000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"publisher","award":["CA200380","W81XWH-21-1-0605","P30-CA051008"],"award-info":[{"award-number":["CA200380","W81XWH-21-1-0605","P30-CA051008"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Georgetown Lombardi Comprehensive Cancer Center Histopathology &amp; Tissue Shared resource and Flow Cytometry center","award":["CA200380","W81XWH-21-1-0605","P30-CA051008"],"award-info":[{"award-number":["CA200380","W81XWH-21-1-0605","P30-CA051008"]}]},{"name":"NIH\/NCI","award":["CA200380","W81XWH-21-1-0605","P30-CA051008"],"award-info":[{"award-number":["CA200380","W81XWH-21-1-0605","P30-CA051008"]}]},{"name":"Georgetown University Master\u2019s Graduate program in Tumor Biology","award":["CA200380","W81XWH-21-1-0605","P30-CA051008"],"award-info":[{"award-number":["CA200380","W81XWH-21-1-0605","P30-CA051008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: New strategies are needed to improve the response to immune checkpoint inhibitors for the treatment of hepatocellular carcinoma. Methods: Mice bearing HCC tumors were treated with PBS (control), a PD-1 antibody (PD-1Ab), proglumide, or the combination of proglumide and the PD-1Ab. The tumor microenvironment (TME) was evaluated histologically for fibrosis and by immunohistochemistry for immune cells. To investigate the mechanisms involved in T-cell efficiency, mouse spleen cells were isolated and examined for T-cell exhaustion markers and cytokine release. The mouse microbiome was analyzed using whole-genome sequencing before therapy and at the end of the study. Results: The combination of proglumide with a PD-1Ab decreased tumoral fibrosis better than monotherapy, and altered the immune cell signature in the TME by decreasing M2-polarized macrophages and increasing the influx of CD8+ T-cells. Proglumide monotherapy or in combination with the PD-1Ab decreased T-cell exhaustion markers and improved cytokine release. The combination therapy resulted in changes to the microbiome, including increased beneficial bacteria and genera known to enhance the efficacy of ICIs. Conclusions: Co-administration of proglumide with ICIs resulted in remodeling of the TME, changing a \u201ccold\u201d tumor to a \u201chot\u201d immune-responsive tumor, activating T-cells, and altering the host microbiome to a population of bacteria that are beneficial.<\/jats:p>","DOI":"10.3390\/cancers17182998","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T09:43:41Z","timestamp":1757929421000},"page":"2998","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanistic Insights into Proglumide\u2019s Role in Immune Cell Efficacy and Response to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"17","author":[{"given":"Priyanka S.","family":"Doneparthi","sequence":"first","affiliation":[{"name":"Department of Oncology, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenqiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyu","family":"Dou","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6173-9082","authenticated-orcid":false,"given":"Hong-Bin","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Georgetown University, Washington, DC 20007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0835-4802","authenticated-orcid":false,"given":"Jill. 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