Tumor-Derived Extracellular\nVesicles Enable Tumor\nTropism Chemo-Genetherapy for Local Immune Activation in Triple-Negative\nBreast Cancer

Triple-negative breast cancer (TNBC) is highly heterogeneous,\nlacks\naccessible therapeutic targets, and features an immunosuppressive\ntumor microenvironment (TME). Anthracycline-based chemotherapy remains\nthe primary treatment method for TNBC, while the current popular immune\ncheckpoint inhibitors persistently encounter therapeutic resistance.\nTherefore, there is an urgent need to explore combined therapeutic\nstrategies to remodel the TME and improve the treatment response.\nConsidering the highly specific homing ability of tumor cell-derived\nvesicles and the key role of the signal transduction and activation\nof the transcription factor 3 (STAT3) pathway in TNBC, we propose\na synergistic therapeutic strategy that integrates gene therapy, chemotherapy,\nand immunotherapy based on STAT3 short interfering RNA (siSTAT3) and\ndoxorubicin (DOX)-functionalized tumor-derived extracellular vesicles\n(TEVs) (siSTAT3-DOX@TEV). The in vitro and in vivo results demonstrate\nthat siSTAT3-DOX@TEV target tumor tissues precisely, downregulate\nSTAT3 expression, and synergistically and efficiently induce immunogenic\ndeath, thereby reversing the immunosuppressive TME. Moreover, mass\ncytometry and immunohistochemistry reveal the local immune activation\neffect of siSTAT3-DOX@TEV, with a significant increase in M1 macrophages,\nCD4<sup>+</sup> T cells, and CD8<sup>+</sup> T cells in tumor tissues.\nThese results provide strong hints for the development of TEV-based\nchemo-gene therapeutic agents for TNBC treatment at the clinical level.