CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: STAR0602 is a selective bifunctional T cell agonist targeting Vβ6/Vβ10 T-cell receptors fused to interleukin-2, with emerging clinical activity in anti-PDL1-resistant tumors. Its murine surrogate, mSTAR1302, expands Vβ13 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. METHODS: 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. RESULTS: 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 Vβ13+ 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. CONCLUSIONS: These findings identify a mechanistic axis in which docetaxel-induced tumor sensitization via TRAIL-R2 cooperates with Vβ-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-mediated tumor sensitization as a mechanistically defined strategy to enhance immunotherapy efficacy in immune-excluded tumors.