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HLA-A*02:01-restricted MAEL peptides were used to pulse monocyte-derived dendritic cells (DCs), which primed cytotoxic T lymphocytes (CTLs). The CTL cytotoxicity against HCC cells was tested. HCC cells were treated with the HDAC inhibitor vorinostat to enhance MAEL expression, and its impact on CTL killing was evaluated. The triple combination (MAEL specific CTLs\u2009+\u2009vorinostat\u2009+\u2009anti-TIGIT) was tested in HCC\u00a0xenograft mouse models, with analyses of tumor growth, survival, and immune infiltration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MAEL was confirmed as an HCC-associated antigen with restricted normal tissue expression. MAEL peptide-pulsed DCs generated potent CTLs with cytotoxicity against HLA-A*02:01\u207a HCC lines. Vorinostat upregulated MAEL expression, enhancing CTL killing (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). In vivo, the dual combination (MAEL specific CTLs\u2009+\u2009vorinostat) outperformed monotherapies, reducing tumor growth and prolonging survival. The triple combination achieved the strongest anti-tumor effects, with significant regression and extended survival, via increased activated MAEL specific CD8\u207a T cell infiltration and enhanced CTL effector functions (elevated IFN-\n                      <jats:italic>\u03b3<\/jats:italic>\n                      , TNF-\n                      <jats:italic>\u03b1<\/jats:italic>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This triple combination strategy synergistically enhances HCC immunotherapy. Vorinostat induces MAEL expression to \u201cunmask\u201d tumors, while TIGIT blockade overcomes T cell exhaustion, amplifying antigen-specific CTL activity. This approach shows promise for HCC treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00262-026-04410-2","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:12:08Z","timestamp":1779207128000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vorinostat unmasks MAEL to enhance DC vaccine-induced CTL killing in hepatocellular carcinoma, potentiated by TIGIT checkpoint inhibition"],"prefix":"10.1007","volume":"75","author":[{"given":"Can","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianru","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenpeng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengya","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiandong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"issue":"3","key":"4410_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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