{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:05:17Z","timestamp":1784009117368,"version":"3.55.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>NADPH oxidase 1 inhibition (NOX1i) has shown to alter the tumor microenvironment in conventional mouse models for hepatocellular carcinoma (HCC). However, clinical translation is hampered by low translatability of these models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We developed two novel human immune system (HIS) mouse models, co-transplanted with orthotopic human HCC cells, to investigate NOX1i in the context of human HCC and human adaptive (T cell-HIS-HCC) or innate (Myeloid-HIS-HCC) immune responses. Mice received NOX1i or vehicle twice per week for 3\u00a0weeks. Results were validated in\n                      <jats:italic>ex vivo<\/jats:italic>\n                      patient-derived precision-cut tumor slices (PCTS).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      T cell-HIS-HCC mice were mainly reconstituted with human T cells. Interestingly, the expression of cytokines and markers involved in both cancer progression and anti-tumor immunity was significantly lower in tumors of NOX1i-treated mice. In the Myeloid-HIS-HCC model, humanization in livers and tumors was dominated by macrophages. Significantly lower human immune cells were observed in tumors of NOX1i-treated Myeloid-HIS-HCC mice, in line with reduced\n                      <jats:italic>VCAM1<\/jats:italic>\n                      and\n                      <jats:italic>ICAM1<\/jats:italic>\n                      expression. NOX1i-treated Myeloid-HIS-HCC mice showed a similar shift in tumor-promoting cytokines and immune checkpoints as NOX1i-treated T cell-HIS-HCC mice. Moreover, gene expression of tumor-associated macrophage, HCC and proliferation markers tended to be lower in tumors of NOX1i-treated Myeloid-HIS-HCC mice\n                      <jats:italic>. Ex vivo<\/jats:italic>\n                      patient-derived PCTS treated with NOX1i also demonstrated lower gene expression of pro-tumorigenic cytokines and tumor-promoting markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data show that NOX1i modulates the tumor-immune microenvironment in human immune system HCC models, and might hold potential in combination therapy to rebalance the dysregulated immune profile in HCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1808515","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:40:30Z","timestamp":1784007630000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Harnessing human immune system models to validate NADPH oxidase 1 inhibition as treatment for 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