{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T15:52:14Z","timestamp":1793116334446,"version":"4.5.0"},"reference-count":47,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"unspecified","delay-in-days":11,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Startup Fund for Scientific Research, Fujian Medical University","award":["2024QH2001"],"award-info":[{"award-number":["2024QH2001"]}]},{"name":"Joint Funds for the innovation of science and Technology, Fujian province","award":["2021Y9036"],"award-info":[{"award-number":["2021Y9036"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82073350"],"award-info":[{"award-number":["82073350"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82102939"],"award-info":[{"award-number":["82102939"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Major Scientific Research Program for Young and Middleaged Health Professionals of Fujian Province","award":["2023ZQNKD013"],"award-info":[{"award-number":["2023ZQNKD013"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,12,19]]},"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Although immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with certain cancers, their efficacy is largely confined to \u201chot\u201d tumors characterized by robust infiltration of tumor-specific CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Conversely, tumors expressing B7-H4 often exhibit an immunologically \u201ccold\u201d tumor microenvironment with poor T cell infiltration, contributing to primary resistance to programmed cell death protein 1 (PD-1) blockade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated the association between B7-H4 expression and clinical outcomes in ICI-treated patients using public immunotherapy datasets. The role of B7-H4 in mediating resistance to PD-1 therapy was examined in mouse tumor models. A fully human anti-B7-H4 monoclonal antibody (clone A8) was generated via phage display screening from a non-immunized human single-chain variable fragment library. In vitro assays assessed antibody-induced tumor cell death and immune activation, while in vivo efficacy was tested in MC38-mH4 and SKOV3-hH4 tumor models, as well as human colorectal cancer organoids. Statistical analyses included Student\u2019s t-test, one-way analysis of variance, and Kaplan-Meier survival analysis, with p&lt;0.05 considered significant.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      High B7-H4 expression was associated with inferior prognosis in patients receiving ICI therapy. In MC38-mH4 tumors, B7-H4 expression conferred resistance to anti-PD-1 treatment. We identified A8, a novel antibody targeting the IgV-like domain of B7-H4, with cross-reactivity to both human and mouse B7-H4. A8-hIgG1 and its Fab fragment induced dynamin-dependent endocytosis of B7-H4, resulting in lysosomal accumulation, altered lysosomal membrane permeabilization and intracellular acidification, ultimately triggering ferroptosis, a form of immunogenic cell death. A8 binding was enhanced under acidic conditions (pH 5.5), promoting lysosome-dependent degradation of B7-H4. A8-induced ferroptosis enhanced dendritic cell maturation, macrophage phagocytosis, and T cell activation. In vivo, A8 promoted CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell and HER2 chimeric antigen receptor-T cell infiltration, inhibited tumor growth, and synergized with PD-1 blockade to overcome primary resistance in multiple preclinical models. This immunogenic and lysosome-dependent cell death mechanism was unique to A8 among the anti-B7-H4 antibodies tested.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study identifies a novel mechanism by which a fully human anti-B7-H4 antibody induces lysosome-dependent immunogenic tumor cell death. These findings support the therapeutic potential of A8 as a single agent or in combination with PD-1 blockade to overcome immune resistance in B7-H4-expressing \u201ccold\u201d tumors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013317","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T15:40:15Z","timestamp":1768232415000},"page":"e013317","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Fully human anti-B7-H4 antibody induces lysosome-dependent ferroptosis to reverse primary resistance to PD-1 blockade"],"prefix":"10.1136","volume":"14","author":[{"given":"Renlu","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China"},{"name":"The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 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