{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T08:34:22Z","timestamp":1775032462992,"version":"3.50.1"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"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>HER2-positive cancers present challenges of drug resistance, toxicity, and immune tolerance. HER2-targeted peptide vaccines have failed clinically, while nucleoside-modified mRNA-lipid nanoparticle (mRNA-LNP) vaccines show promise for robust antitumor immunity. This study utilized heterologous immunity (rat HER2 extracellular domain, rHER2 ECD) to circumvent HER2 tolerance, developing a safe mRNA-LNP vaccine and exploring its synergy with anti-PD-1 therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We synthesized N1-methyl-pseudouridine (m1\u03c8)-modified mRNAs, encoding either rHER2 ECD alone (rHER2 ECD mRNA-LNP) or rHER2 ECD fused to murine IFN\u03b3 (rHER2 ECD-IFN\u03b3 mRNA-LNP), and then encapsulated them in LNPs via microfluidic mixing. BALB\/c mice were immunized on days 1, 15, 29, then challenged with HER2-overexpressing 4T1 (4T1-HER2) cells 2 weeks post-final immunization. Efficacy was assessed by tumor growth, immune responses via flow cytometry, ELISA, ELISpot and cytotoxicity assays, safety via body\/organ weight and serum markers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HER2 ECD mRNA-LNPs exhibited &amp;gt;80% encapsulation efficiency and narrow particle size distribution. As monotherapy, rHER2 ECD mRNA-LNPs induced high anti-HER2 antibody titers, polyfunctional CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells (IFN\u03b3\n                      <jats:sup>+<\/jats:sup>\n                      \/TNF\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      ), and durable memory T cells, achieving 87.0% tumor inhibition. This inhibition rate was significantly higher than that of the rHER2 ECD-IFN\u03b3 mRNA-LNP variant, which achieved 21.9% tumor inhibition and induced anti-IFN\u03b3 neutralizing antibodies. Combination with anti-PD-1 monoclonal antibody (mAb) further enhanced tumor inhibition, with 2\/6 tumors failing to establish. This synergy was driven by tissue-resident memory T (T\n                      <jats:sub>RM<\/jats:sub>\n                      ) cell enrichment in the tumor microenvironment (TME), which reached 15.2% in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells and 12.9% in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. No systemic toxicity was observed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The rHER2 ECD mRNA-LNP effectively circumvents HER2-specific immune tolerance. As a potent and safe platform, it induces robust coordinated humoral and cellular immunity and significantly enhances checkpoint blockade efficacy via the enrichment of T\n                      <jats:sub>RM<\/jats:sub>\n                      cells in the TME, which underscores its promising potential for the treatment of HER2-positive cancers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1737558","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T05:41:41Z","timestamp":1775022101000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Robust CD8+ T cell responses induced by an mRNA-LNP vaccine encoding rat HER2 extracellular domain confer prophylactic tumor protection"],"prefix":"10.3389","volume":"17","author":[{"given":"Kexin","family":"Li","sequence":"first","affiliation":[{"name":"Research Center, The Key Laboratory of Tumor Prevention and Precise Diagnosis & Treatment in Hebei Province, the Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]},{"name":"Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences","place":["Jinan, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoya","family":"Li","sequence":"additional","affiliation":[{"name":"Research Center, The Key Laboratory of Tumor Prevention and Precise Diagnosis & Treatment in Hebei Province, the Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research Center, The Key Laboratory of Tumor Prevention and Precise Diagnosis & Treatment in Hebei Province, the Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suli","family":"Dai","sequence":"additional","affiliation":[{"name":"Research Center, The Key Laboratory of Tumor Prevention and Precise Diagnosis & Treatment in Hebei Province, the Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Li","sequence":"additional","affiliation":[{"name":"Research Center, The Key Laboratory of Tumor Prevention and Precise Diagnosis & Treatment in Hebei Province, the Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Hebei Clinical Research Center for Radiation Oncology, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, 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