Synergistic chemoimmunotherapy using pirarubicin-loaded tumor-derived extracellular vesicles for triple-negative breast cancer (TNBC)

Abstract

Triple-negative breast cancer (TNBC) has an extremely poor clinical prognosis due to the lack of effective therapeutic targets and high heterogeneity. In this study, we developed a synergistic chemoimmunotherapy based on tumor-derived extracellular vesicles (TEVs), which induces immunogenic cell death (ICD) and remodels the immunosuppressive tumor microenvironment (TME) by delivering pirarubicin (THP). 4T1 TNBC cell derived TEVs were loaded with THP via overnight co-incubation at room temperature (THP@TEVs), which exhibited excellent tumor targeting and biocompatibility. In vitro experiments demonstrated that THP@TEVs was efficiently internalized by tumor cells, and compared to the free THP group, THP@TEVs significantly increased the apoptosis rate (70.25 % vs. 25.61 %, p < 0.001, n = 3)”. In vivo studies showed that THP@TEVs significantly activated the ICD effect and promoted CD8⁺ T-cell infiltration by enhancing calreticulin (CRT) membrane translocation and high mobility group protein B1 (HMGB1) release (CRT increased≈3 fold; HMGB1 increased≈3.1 fold). In addition, compared with the control group, the tumor volume in the THP@TEVs group was reduced by approximately 62.1 % (p < 0.001, n = 5) and no histopathological changes were observed in major organs (such as heart, liver, spleen, lungs, and kidneys) upon H&E staining. This study provides a precise, low-toxicity chemotherapy and immune synergistic strategy for TNBC and expands the potential of TEVs in tumor therapy.