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This study aims to establish a patient-derived tumor organoid-immune cell coculture system to evaluate \u03b3\u03b4 T-cell reactivity and cytotoxicity in a human-relevant TME (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200910 PDTO lines;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20093 independent experiments).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We developed an innovative coculture system\u2014believed to be the first to integrate patient-derived tumor organoids (PDTOs) and autologous tumor-infiltrating lymphocytes (TILs) or healthy donor-derived allogeneic V\u03b39V\u03b42 T cell. T-cell activation was quantified by comparing CD137 expression on \u03b3\u03b4 T cells versus CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells via flow cytometry after coculture. The cytotoxicity of V\u03b39V\u03b42 T cells was evaluated at various effector-to-target (E:T) ratios using a live-cell imaging assay to track BCO infiltration and apoptosis over 24\u2009hours. Secreted effector molecules (IFN-\u03b3, granzyme B, perforin) were measured from coculture supernatants using a cytometric bead array.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Baseline analysis revealed that \u03b3\u03b4 T cells represent the most reactive subset within expanded TILs, with 12.3% expressing CD137 compared to 3.49% of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0118). Notably, autologous BCO\u2013TIL coculture preferentially enhanced \u03b3\u03b4 T-cell activation, reaching 24.85% CD137\n                      <jats:sup>+<\/jats:sup>\n                      \u2014a frequency significantly higher than that of CD8 (9.15%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0062) and CD4 (9.99%) subsets. The net increase in CD137 positivity for \u03b3\u03b4 T cells was more than double that of CD8 T cells (12.55% vs. 5.66%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0467). Allogeneic V\u03b39V\u03b42 T cells demonstrated significant, dose-dependent cytotoxicity against BCOs (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). Maximal cell death (RFU fold-change: 5.2\u2009\u00b1\u20090.5) was achieved at an effector-to-target (E:T) ratio of 10:1 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). This cytotoxic efficacy was highly correlated with the secretion of lytic effectors, including IFN-\u03b3 (\u2009&gt;\u20091000\u2009pg\/mL;\n                      <jats:italic>p<\/jats:italic>\n                      &lt;\u20090.001), granzyme B (\u2009&gt;\u20092000\u2009pg\/mL), and perforin (\u2009&gt;\u2009350\u2009pg\/mL).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings demonstrate that 3D autologous coculture leads to the preferential stimulation of \u03b3\u03b4 T cells, establishing them as a primary reactive subset capable of bypassing MHC-restriction bottlenecks. The potent dismantling of tumor architecture by allogeneic V\u03b39V\u03b42 T cells, supported by high-resolution kinetic and cytokine data, substantiates their development as \u201coff-the-shelf\u201d therapies. Collectively, this platform provides a standardized, high-fidelity engine for the rapid preclinical assessment of next-generation cellular immunotherapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-07706-0","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T09:25:40Z","timestamp":1777109140000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Analysis of the tumor reactivity of autologous TILs and allogeneic \u03b3\u03b4 T cells via tumor organoid\u2013immune cell coculture"],"prefix":"10.1186","volume":"24","author":[{"given":"Zijun","family":"Su","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haishan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongdong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanxi","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanchan","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weili","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhinan","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"7706_CR1","doi-asserted-by":"crossref","unstructured":"Ali I, Alsehli M, Scotti L, Tullius Scotti M, Tsai S, Yu R, et al. 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Written informed consent was obtained from all participating patients prior to tissue collection. The consent process included detailed explanations of the study purpose, procedures, potential risks, and safeguards for data anonymity. All patient-derived samples (tumor tissues, adjacent normal tissues, and peripheral blood) were handled under strict compliance with institutional ethical guidelines for human specimen research.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"595"}}