{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T05:59:18Z","timestamp":1776405558745,"version":"3.51.2"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Human papillomavirus (HPV) infection is strongly associated with multiple malignancies, primarily driven by the viral oncoproteins E6 and E7, which play a central role in HPV-induced malignant transformation. Although current prophylactic HPV vaccines have shown remarkable efficacy in preventing initial infections, there remains an urgent need for therapeutic vaccines targeting pre-existing HPV infections and HPV-associated malignancies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, we developed TriStim-E6\/E7, a novel HPV mRNA vaccine that combines E6\/E7 antigens with three T cell co-stimulatory molecules (CD80, 4-1BBL, and CD70). The TriStim-E6\/E7 mRNA was encapsulated in lipid nanoparticles (LNPs) and administered intramuscularly to mice, followed by analysis of cellular immunogenicity. The anti-tumor efficacy of TriStim-E6\/E7 mRNA was evaluated using an HPV-positive TC-1 tumor model.\n                      <jats:italic>In vitro<\/jats:italic>\n                      T cell activation and proliferation assays were conducted to investigate the mechanistic underpinnings of the vaccine. Additionally, safety was assessed in a PBMC-reconstituted mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Administration of TriStim-E6\/E7 mRNA elicited robust antigen-specific cellular immune responses and achieved complete regression of HPV-positive TC-1 tumors in a syngeneic mouse model. The vaccine also demonstrated durable immunoprotection, preventing tumor recurrence upon rechallenge. Through targeted T cell depletion experiments, we established that CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells are indispensable for the vaccine\u2019s anti-tumor activity, whereas CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell depletion had no significant impact on therapeutic outcomes. Treatment with TriStim-E6\/E7 mRNA significantly induced the proliferation and tumor infiltration of E7 antigen-specific T cells. Mechanistic investigations revealed that TriStim-E6\/E7 mRNA significantly enhanced T cell activation and proliferation\n                      <jats:italic>in vitro<\/jats:italic>\n                      compared to control mRNAs lacking co-stimulatory elements. Furthermore, combination therapy with anti-PD-L1 antibody synergistically enhanced the anti-tumor efficacy of TriStim-E6\/E7 mRNA. To evaluate clinical translatability, we developed a humanized version (hTriStim-E6\/E7) encoding human CD80, 4-1BBL, and CD70 co-stimulatory molecules together with HPV E6\/E7 fusion proteins. This humanized construct effectively induced antigen-specific cellular immune responses and suppressed tumor growth in CD28\/4-1BB\/CD27 triple-humanized mice. Additionally, a \u201ccytokine release storm\u201d experiment using PBMC-reconstituted mice confirmed a favorable safety profile of TriStim-E6\/E7 mRNA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings collectively demonstrate the promising therapeutic potential of TriStim\u2212E6\/E7 mRNA for clinical translation against HPV\u2212associated malignancies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1823374","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T05:23:06Z","timestamp":1776403386000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel mRNA-based therapeutic vaccine elicits robust anti-tumor immunity against HPV-associated malignancies"],"prefix":"10.3389","volume":"17","author":[{"given":"Qi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Research and Development, Liverna Therapeutics Inc.","place":["Zhuhai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongzhuang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Research and Development, Liverna Therapeutics Inc.","place":["Zhuhai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Research and Development, Liverna Therapeutics Inc.","place":["Zhuhai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhigang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Research and Development, Liverna Therapeutics Inc.","place":["Zhuhai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"102","DOI":"10.3390\/vaccines11010102","article-title":"Tracking HPV infection, associated cancer development, and recent treatment efforts-a comprehensive review","volume":"11","author":"Malik","year":"2023","journal-title":"Vaccines"},{"key":"B2","article-title":"Review of HPV-related diseases and cancers","volume":"40","author":"Brianti","year":"2017","journal-title":"New Microbiologica"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(10)70230-8","article-title":"Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study","volume":"11","author":"de Sanjose","year":"2010","journal-title":"Lancet Oncol"},{"key":"B4","volume-title":"IARC handbooks of cancer prevention. 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