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Vaccination with MHC-II-restricted tumor epitopes impart superior protection compared to an immunodominant MHC-I epitope, prompting development of MHC-II affinity-enhanced tetramers to track tumor-specific CD4 T cells. As tumors progress, tumor-specific CD4 T cells decline, and remaining cells acquire features of regulation. Agonistic anti-CD40 increases Th1 cell clonal expansion and transiently decreases Tregs. Anti-PD-L1 promotes Tfh clonal expansion in draining lymph nodes and tumor while preventing Treg rebound after anti-CD40. Treatment with anti-CD40 promotes intratumoral Stat1\n                  <jats:sup>+<\/jats:sup>\n                  macrophages, tertiary lymphoid structures (TLS), and immune triads. MHC-II on myeloid cells but not B cells is required for immunotherapy-induced TLS formation and antitumor effects. IL-15 complex enhances immunotherapy-induced Th1 effectors without promoting Tregs. Human immunotherapy transcriptomics shows conserved Th1 programming and Treg destabilization as a feature of response. Thus, tumor-specific CD4 T cells are central mediators of effective immunotherapy in solid tumors.\n                <\/jats:p>","DOI":"10.64898\/2026.07.28.741325","type":"posted-content","created":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T18:25:16Z","timestamp":1785695116000},"source":"Crossref","is-referenced-by-count":0,"title":["Tumor-specific CD4 T cells cooperate with myeloid cells to remodel the pancreatic tumor microenvironment and enable effective immunotherapy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3279-133X","authenticated-orcid":false,"given":"Eduardo","family":"Cruz-Hinojoza","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA"},{"name":"Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, 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