{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T07:08:58Z","timestamp":1788851338698,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20H03474"],"award-info":[{"award-number":["20H03474"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K27397"],"award-info":[{"award-number":["23K27397"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22ama221306"],"award-info":[{"award-number":["JP22ama221306"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22fk0310509"],"award-info":[{"award-number":["JP22fk0310509"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP25fk0310531"],"award-info":[{"award-number":["JP25fk0310531"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP26ck0106121"],"award-info":[{"award-number":["JP26ck0106121"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The clinical success of immune checkpoint inhibitors (ICI) has shifted the paradigm of cancer treatment, yet the fundamental mechanisms governing the long\u2010term sustainability of antitumor T\u2010cell responses remain elusive. Emerging evidence suggests that the efficacy of ICI depends not only on the reinvigoration of pre\u2010existing tumor\u2010infiltrating lymphocytes but also on the continuous mobilization and replacement of T\u2010cell clones from systemic reservoirs. In this review, we propose a \u201cspatiotemporal ecosystem model\u201d of the antitumor T\u2010cell response. We first delineate the spatial dynamics of T\u2010cell clones, where tumor\u2010reactive progenitors primed in the tumor\u2010draining lymph nodes (dLN) circulate through the peripheral blood to replenish the tumor microenvironment (TME). We highlight that TCR avidity emerges as a key determinant of clonal fate; while high\u2010avidity clones provide potent early cytotoxicity, their susceptibility to accelerated terminal exhaustion eventually creates an available niche that allows for the subsequent expansion of intermediate\u2010avidity successor clones. Furthermore, we discuss how single\u2010cell multi\u2010omics integration (transcriptome, TCR repertoire, and epigenome) reveals that clonal fate is functionally encoded in the molecular and metabolic poise of T cells prior to their expansion. Finally, we discuss the potential of monitoring these clonal dynamics through liquid biopsy as a non\u2010invasive window into the resilience of the immune ecosystem, distinguishing responders with sustainable, polyclonal mobilization from non\u2010responders with frustrated, oligoclonal responses. By integrating clonal evolution, metabolic fitness, and inter\u2010organ crosstalk, this ecosystem perspective offers a comprehensive framework for predicting therapeutic outcomes and developing next\u2010generation precision immunotherapies.<\/jats:p>","DOI":"10.1111\/cas.70531","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T06:38:51Z","timestamp":1788849531000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatiotemporal\n                    <scp>CD8<\/scp>\n                    <sup>+<\/sup>\n                    T\u2010Cell Dynamics: Clonal Replacement and Expansion as Determinants of Sustainable Antitumor Response"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3871-9921","authenticated-orcid":false,"given":"Satoshi","family":"Ueha","sequence":"first","affiliation":[{"name":"Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences Tokyo University of Science  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyasu","family":"Aoki","sequence":"additional","affiliation":[{"name":"Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences Tokyo University of Science  Chiba Japan"},{"name":"Vaccine &amp; Infectious Disease Division (VIDD) Fred Hutchinson Cancer Center  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munetomo","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Preventive Medicine, Graduate School of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeyuki","family":"Shichino","sequence":"additional","affiliation":[{"name":"Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences Tokyo University of Science  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouji","family":"Matsushima","sequence":"additional","affiliation":[{"name":"Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences Tokyo University of Science  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"crossref","DOI":"10.1007\/s12672-025-04361-7","article-title":"Immune Checkpoint Blockade in Cancer: Current Insights and Future Horizons","volume":"17","author":"Saman H.","year":"2026","journal-title":"Discover Oncology"},{"key":"e_1_2_16_3_1","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1158\/0008-5472.CAN-23-2006","article-title":"A Large\u2010Scale Meta\u2010Analysis Reveals Positive Feedback Between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy","volume":"84","author":"Yang J.","year":"2024","journal-title":"Cancer Research"},{"key":"e_1_2_16_4_1","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.cell.2023.02.021","article-title":"Dynamic CD8(+) T Cell Responses to Cancer Immunotherapy in Human Regional Lymph Nodes Are Disrupted in Metastatic Lymph Nodes","volume":"186","author":"Rahim M. K.","year":"2023","journal-title":"Cell"},{"key":"e_1_2_16_5_1","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1038\/s41591-019-0522-3","article-title":"Clonal Replacement of Tumor\u2010Specific T Cells Following PD\u20101 Blockade","volume":"25","author":"Yost K. E.","year":"2019","journal-title":"Nature Medicine"},{"key":"e_1_2_16_6_1","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1038\/s41467-024-46450-1","article-title":"Spatial Relationships in the Urothelial and Head and Neck Tumor Microenvironment Predict Response to Combination Immune Checkpoint Inhibitors","volume":"15","author":"Gil\u2010Jimenez A.","year":"2024","journal-title":"Nature Communications"},{"key":"e_1_2_16_7_1","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s12943-025-02294-x","article-title":"Dual Role of Interferon\u2010Gamma in the Response of Melanoma Patients to Immunotherapy With Immune Checkpoint Inhibitors","volume":"24","author":"Wawrzyniak P.","year":"2025","journal-title":"Molecular Cancer"},{"key":"e_1_2_16_8_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.xgen.2025.100842","article-title":"Single\u2010Cell Meta\u2010Analysis of T Cells Reveals Clonal Dynamics of Response to Checkpoint Immunotherapy","volume":"5","author":"Shorer O.","year":"2025","journal-title":"Cell Genomics"},{"key":"e_1_2_16_9_1","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1158\/2326-6066.CIR-22-0517","article-title":"Clonal Spreading of Tumor\u2010Infiltrating T Cells Underlies the Robust Antitumor Immune Responses","volume":"11","author":"Aoki H.","year":"2023","journal-title":"Cancer Immunology Research"},{"key":"e_1_2_16_10_1","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.ccell.2023.03.009","article-title":"Lineage Tracing Reveals Clonal Progenitors and Long\u2010Term Persistence of Tumor\u2010Specific T Cells During Immune Checkpoint Blockade","volume":"41","author":"Pai J. A.","year":"2023","journal-title":"Cancer Cell"},{"key":"e_1_2_16_11_1","doi-asserted-by":"crossref","first-page":"9175","DOI":"10.1038\/s41467-025-64107-5","article-title":"A Pan\u2010Immunotherapy Signature to Predict Intratumoral CD8(+) T Cell Expansions","volume":"16","author":"Takahashi M.","year":"2025","journal-title":"Nature Communications"},{"key":"e_1_2_16_12_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.smim.2020.101435","article-title":"Memory CD8(+) T Cell Responses to Cancer","volume":"49","author":"Han J.","year":"2020","journal-title":"Seminars in Immunology"},{"key":"e_1_2_16_13_1","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1111\/cas.14975","article-title":"Greater Extent of Blood\u2010Tumor TCR Repertoire Overlap Is Associated With Favorable Clinical Responses to PD\u20101 Blockade","volume":"112","author":"Aoki H.","year":"2021","journal-title":"Cancer Science"},{"key":"e_1_2_16_14_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.807696","article-title":"Revealing Clonal Responses of Tumor\u2010Reactive T\u2010Cells Through T Cell Receptor Repertoire Analysis","volume":"13","author":"Aoki H.","year":"2022","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_16_15_1","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1158\/2326-6066.CIR-20-0989","article-title":"Transient Depletion of CD4(+) Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer","volume":"9","author":"Aoki H.","year":"2021","journal-title":"Cancer Immunology Research"},{"key":"e_1_2_16_16_1","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.immuni.2022.03.006","article-title":"Type 1 Conventional Dendritic Cells Maintain and Guide the Differentiation of Precursors of Exhausted T Cells in Distinct Cellular Niches","volume":"55","author":"Dahling S.","year":"2022","journal-title":"Immunity"},{"key":"e_1_2_16_17_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.744381","article-title":"Proportional Tumor Infiltration of T Cells via Circulation Duplicates the T Cell Receptor Repertoire in a Bilateral Tumor Mouse Model","volume":"12","author":"Tsunoda M.","year":"2021","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_16_18_1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.immuni.2016.07.021","article-title":"T Cell Factor 1\u2010Expressing Memory\u2010Like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections","volume":"45","author":"Utzschneider D. 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Cancer"},{"key":"e_1_2_16_24_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1186\/s40425-019-0677-y","article-title":"First\u2010In\u2010Human Phase 1 Study of IT1208, a Defucosylated Humanized Anti\u2010CD4 Depleting Antibody, in Patients With Advanced Solid Tumors","volume":"7","author":"Shitara K.","year":"2019","journal-title":"Journal for Immunotherapy of Cancer"},{"key":"e_1_2_16_25_1","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1038\/s41590-022-01337-5","article-title":"Divergent Clonal Differentiation Trajectories of T Cell Exhaustion","volume":"23","author":"Daniel B.","year":"2022","journal-title":"Nature Immunology"},{"key":"e_1_2_16_26_1","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/s41590-024-02044-z","article-title":"Low\u2010Avidity T Cells Drive Endogenous Tumor Immunity in Mice and Humans","volume":"26","author":"Singhaviranon S.","year":"2025","journal-title":"Nature Immunology"},{"key":"e_1_2_16_27_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1136\/jitc-2023-007114","article-title":"Reactivation of Low Avidity Tumor\u2010Specific CD8(+) T Cells Associates With Immunotherapeutic Efficacy of Anti\u2010PD\u20101","volume":"11","author":"Sugiyarto G.","year":"2023","journal-title":"Journal for Immunotherapy of Cancer"},{"key":"e_1_2_16_28_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20220679"},{"key":"e_1_2_16_29_1","doi-asserted-by":"crossref","DOI":"10.1002\/eji.202350700","article-title":"Zfp36l1 Establishes the High\u2010Affinity CD8 T\u2010Cell Response by Directly Linking TCR Affinity to Cytokine Sensing","volume":"54","author":"Petkau G.","year":"2024","journal-title":"European Journal of Immunology"},{"key":"e_1_2_16_30_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2020.00624","article-title":"Regulation of T Helper Cell Fate by TCR Signal Strength","volume":"11","author":"Bhattacharyya N. 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Cancer"},{"key":"e_1_2_16_37_1","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/s41590-020-00834-9","article-title":"Mitochondrial Stress Induced by Continuous Stimulation Under Hypoxia Rapidly Drives T Cell Exhaustion","volume":"22","author":"Scharping N. E.","year":"2021","journal-title":"Nature Immunology"},{"key":"e_1_2_16_38_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2025.1711328","article-title":"Metabolism of Tumor Infiltrating T Cells","volume":"16","author":"Ertl H. 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