Salidroside-Loaded, TMTP1-Modified CSC-Exosomes Reprogram the PI3K/AKT/mTOR Axis to Overcome PD-1 Resistance in Breast Cancer

Purpose: To elucidate how Salidroside-loaded, oligopeptide-modified tumor exosomes (Salidroside@T-exo) rewire the PI3K/AKT/mTOR axis to remodel the immune microenvironment (IME) and reverse acquired PD-1 resistance in breast cancer. Materials and Methods: CSC-exosomes were surface-engineered with TMTP1 peptide and electroporated with Salidroside. PD-1-resistant MA782/5s-8101-R cells and an orthotopic mouse model were used. Multi-omics, flow cytometry, ELISA, immunofluorescence, in vivo imaging, and molecular assays examined immune and signaling outcomes. Results: Salidroside@T-exo restored T-cell IFN-γ and GZMB secretion, suppressed CD8+ T-cell apoptosis, and inhibited p-PI3K/p-AKT/p-mTOR in T cells. CSC migration, invasion, and stemness (OCT4, NANOG, SOX2) were markedly reduced. Tumor growth, Ki-67 index, and CSC frequency dropped while TUNEL-positive cells rose. Conclusion: Salidroside@T-exo reverses PD-1 blockade resistance by simultaneously inhibiting PI3K/AKT/mTOR signaling in T cells and eradicating breast CSCs, offering a clinically translatable strategy for refractory breast cancer immunotherapy.