{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:52:54Z","timestamp":1791312774382,"version":"4.3.1"},"reference-count":59,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"unspecified","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Swiss Cancer League","award":["KFS-6233-08-2024"],"award-info":[{"award-number":["KFS-6233-08-2024"]}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["101034170"],"award-info":[{"award-number":["101034170"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bright Peak Therapeutics","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,6,24]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Immune checkpoint inhibitors have revolutionized cancer therapy, yet a substantial proportion of patients exhibit primary or acquired resistance. Immunocytokines offer a strategy to enhance antitumor immunity by delivering cytokine signals selectively to the tumor microenvironment. Here, we describe the immunoconjugate anti-programmed cell death protein 1 (PD-1)-interleukin (IL)-18 (aPD1-IL18\n                      <jats:sub>mut<\/jats:sub>\n                      ), designed to couple PD-1-blockade with localized IL-18-mediated immune activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      aPD1-IL18\n                      <jats:sub>mut<\/jats:sub>\n                      was generated by chemically conjugating the anti-human PD-1 antibody Lipustobart to an IL-18 variant engineered to evade IL-18 binding protein. Its mechanism of action was characterized using human PD-1 transgenic mouse models. To assess the translational relevance of these in vivo findings, complementary in vitro assays were conducted on human tumor samples, alongside analyses of publicly available single-cell RNA sequencing datasets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In vitro, PD-1 engagement enhanced functional IL-18 activity, preserving interferon (IFN)-\u03b3 secretion even under IL-18BP pressure. In MC38 tumors, aPD1-IL18\n                      <jats:sub>mut<\/jats:sub>\n                      induced robust CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell-driven tumor control, accompanied by intratumoral accumulation of activated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and a pronounced type 1-associated cytokine response. In anti-PD-1-resistant YUMM1.7 tumors, therapeutic efficacy instead relied predominantly on Th1-like CD4\n                      <jats:sup>+<\/jats:sup>\n                      effector T cells, and aPD1-IL18\n                      <jats:sub>mut<\/jats:sub>\n                      stimulation was associated with enhanced activation, proliferation, IFN-\u03b3, and granzyme B expression in PD-1\n                      <jats:sup>+<\/jats:sup>\n                      IL-18R\u0251\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. In human cancer digest cultures, aPD1-IL18\n                      <jats:sub>mut<\/jats:sub>\n                      elicited a dominant IL-18\/IFN-\u03b3-driven cytokine signature and enhanced tumor cell killing. Importantly, analyses of the immune infiltrate across multiple human solid tumor types identified analogous PD-1\n                      <jats:sup>+<\/jats:sup>\n                      IL-18R\u0251\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      Th1-like and CD8\n                      <jats:sup>+<\/jats:sup>\n                      effector-like T-cell subsets with effector-associated and tumor-reactive transcriptional and protein signatures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      aPD1-IL18\n                      <jats:sub>mut<\/jats:sub>\n                      activates T-cell populations with tumor-reactive features and promotes IFN-\u03b3-driven inflammation across distinct tumor immune contexts. Its ability to activate CD8\n                      <jats:sup>+<\/jats:sup>\n                      and CD4\n                      <jats:sup>+<\/jats:sup>\n                      Th1-like effector cells, together with the presence of analogous subsets in multiple human cancers, provides mechanistic and translational support for PD-1-targeted IL-18 therapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015090","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:15:16Z","timestamp":1784034916000},"page":"e015090","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Anti-PD1-IL18 immunoconjugate promotes effector T cell-mediated antitumor 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