{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:53:32Z","timestamp":1790124812764,"version":"4.0.1"},"reference-count":50,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"unspecified","delay-in-days":23,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 82502217 to M.Z."],"award-info":[{"award-number":["No. 82502217 to M.Z."]}],"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":["No. 82503111 to S.M."],"award-info":[{"award-number":["No. 82503111 to S.M."]}],"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":["No.82403856 to K.Y."],"award-info":[{"award-number":["No.82403856 to K.Y."]}],"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":["Nos.82071866,82271762 and 82241227 to Y. Zhang"],"award-info":[{"award-number":["Nos.82071866,82271762 and 82241227 to Y. Zhang"]}],"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":["Nos.82072557 and 82372855 to H.L"],"award-info":[{"award-number":["Nos.82072557 and 82372855 to H.L"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Key Research and Development Project of MOST, China","award":["No. 2021YFC2500900 to H.L."],"award-info":[{"award-number":["No. 2021YFC2500900 to H.L."]}]},{"name":"National Key Research and Development Project of MOST, China","award":["No. 2023YFC2411403 to Y. Zhang"],"award-info":[{"award-number":["No. 2023YFC2411403 to Y. Zhang"]}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai Municipality","doi-asserted-by":"publisher","award":["No. 22ZR1454800 to Y. Zhang"],"award-info":[{"award-number":["No. 22ZR1454800 to Y. Zhang"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai Municipality","doi-asserted-by":"publisher","award":["No. 25ZR1402452 to M.Z."],"award-info":[{"award-number":["No. 25ZR1402452 to M.Z."]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,2,7]]},"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Global clinical programs based on TIGIT (T cell immunoglobulin and ITIM domain) blockade have been terminated due to inadequate clinical efficacy. New approaches are needed to increase the antitumor activity of anti-TIGIT-based immunotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Multiomics analyses, including single-cell RNA sequencing (scRNA-seq), single-cell TCR sequencing (scTCR-seq), and The Cancer Genome Atlas bulk RNA-seq, were performed to profile TIGIT and the costimulator CD226 expression and assess intratumoral regulatory T cells (Tregs) clonality, with validation by flow cytometry in murine and patient-derived tumor-infiltrating lymphocytes. The therapeutic efficacy of anti-TIGIT antibodies (\u03b1TIGIT), including \u03b1TIGIT-IgG1-wild-type (WT), \u03b1TIGIT-IgG1-WT with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity (\u03b1TIGIT-IgG1-ADCC), \u03b1TIGIT-IgG4-WT, and tiragolumab, was evaluated in MC38 tumors-inoculated humanized\n                      <jats:italic>TIGIT<\/jats:italic>\n                      knock-in mice (\n                      <jats:italic>\n                        Tigit\n                        <jats:sup>h\/h<\/jats:sup>\n                      <\/jats:italic>\n                      ,\n                      <jats:italic>\n                        Tigit\n                        <jats:sup>h\/m<\/jats:sup>\n                      <\/jats:italic>\n                      ). Tumor microenvironment alterations were analyzed using flow cytometry and scRNA\/TCR-seq. Antibody binding affinity and ADCC activity were assessed via biolayer interferometry and\n                      <jats:italic>in vitro<\/jats:italic>\n                      ADCC assays. Safety profiles were examined in a murine immune-related adverse events model through growth monitoring, survival analysis, and histopathological evaluation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Using mouse models and clinical sample analysis, we identified a population of TIGIT\n                      <jats:sup>high<\/jats:sup>\n                      CD226\n                      <jats:sup>\u2212<\/jats:sup>\n                      clonally expanded intratumoral Tregs as a major barrier limiting the ability of TIGIT blockade to enhance effector cell function. \u03b1TIGIT-IgG1-ADCC specifically targeted and eliminated the TIGIT\n                      <jats:sup>high<\/jats:sup>\n                      CD226\n                      <jats:sup>\u2212<\/jats:sup>\n                      clonally expanded Treg subset, resulting in a marked improvement in antitumor efficacy compared with WT and clinically unsuccessful \u03b1TIGIT. Mechanistically, removal of these Tregs through \u03b1TIGIT-IgG1-ADCC relieved their suppression of stem-like CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, facilitating their differentiation into T helper cell 1 (Th1) effector cells. Th1-derived interferon-gamma (IFN-\u03b3) further enhanced the functionality of tumor-infiltrating CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Importantly, the presence of clonally expanded intratumoral Tregs and the suppression of stem-like CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells correlated with poor immunotherapy response in patients with non-small cell lung cancer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Targeted elimination of clonally expanded intratumoral Tregs is essential to unlock the full therapeutic potential of \u03b1TIGIT. These novel findings provide a key rationale and strategic direction for overcoming the limitations of current \u03b1TIGIT-based cancer immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013636","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T16:10:15Z","timestamp":1771949415000},"page":"e013636","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Specific depletion of TIGIT\n                    <sup>high<\/sup>\n                    CD226\n                    <sup>\u2212<\/sup>\n                    clonally expanded intratumoral Tregs defines safe and effective TIGIT targeting"],"prefix":"10.1136","volume":"14","author":[{"given":"Haoyue","family":"Zhou","sequence":"first","affiliation":[{"name":"Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 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