{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:02:35Z","timestamp":1780470155309,"version":"3.54.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>STAR0602 is a selective bifunctional T cell agonist targeting V\u03b26\/V\u03b210 T-cell receptors fused to interleukin-2, with emerging clinical activity in anti-PDL1\u2013resistant tumors. Its murine surrogate, mSTAR1302, expands V\u03b213 T cells and mediates antitumor activity. Docetaxel, beyond its cytotoxic effects, induces immunogenic modulation of tumor cells. We hypothesized that docetaxel-driven tumor sensitization would enhance susceptibility to immune-mediated killing, while mSTAR1302 would expand functional T cell subsets, resulting in coordinated antitumor responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The therapeutic efficacy and mechanism of action of docetaxel and mSTAR1302 combination therapy were evaluated in 4T1 triple-negative breast cancer and TRAMP-C2 prostate cancer models. Immune profiling, functional assays, and CRISPR-mediated gene knockdown were used to define mechanisms of response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Combination therapy significantly reduced tumor burden and improved survival compared to monotherapies in both models. Docetaxel induced immunogenic modulation characterized by upregulation of MHCI, FAS, and TRAIL-R2, enhancing tumor susceptibility to immune-mediated lysis. Mechanistically, TRAIL-R2 expression contributed substantially to antitumor activity, as knockdown attenuated therapeutic efficacy. mSTAR1302 expanded V\u03b213+ CD4+ and CD8+ tumor-infiltrating lymphocytes and promoted antigen-specific T cell responses. Depletion studies demonstrated that CD4+ T, CD8+ T, and NK cells collectively mediated the antitumor effects of combination therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings identify a mechanistic axis in which docetaxel-induced tumor sensitization via TRAIL-R2 cooperates with V\u03b2-targeted T cell expansion to drive coordinated immune-mediated tumor regression. This work supports the clinical evaluation of STAR0602 in combination with chemotherapy and highlights TRAIL-R2\u2013mediated tumor sensitization as a mechanistically defined strategy to enhance immunotherapy efficacy in immune-excluded tumors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1850760","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:07:17Z","timestamp":1780466837000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Docetaxel enhances V\u03b2-directed T-cell activation and antitumor immunity mediated by a bifunctional TCR agonist in breast and prostate cancer models"],"prefix":"10.3389","volume":"17","author":[{"given":"Jonelle K.","family":"Lee","sequence":"first","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health","place":["Bethesda, MD, United 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