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

Area of Science:

• Oncology
• Immunotherapy
• Nanomedicine

Background:

• Acquired resistance to PD-1 blockade is a major challenge in breast cancer immunotherapy.
• Tumor-derived exosomes can be engineered as drug delivery vehicles.
• Modulating the tumor immune microenvironment (IME) and targeting cancer stem cells (CSCs) are crucial for overcoming resistance.

Purpose of the Study:

• To investigate how Salidroside-loaded, oligopeptide-modified tumor exosomes (Salidroside@T-exo) reverse acquired PD-1 resistance in breast cancer.
• To elucidate the mechanism of Salidroside@T-exo in remodeling the IME by targeting the PI3K/AKT/mTOR axis.

Main Methods:

• Surface engineering of exosomes with TMTP1 peptide and loading with Salidroside.
• Utilizing PD-1-resistant breast cancer cell lines and an orthotopic mouse model.
• Employing multi-omics, flow cytometry, ELISA, immunofluorescence, in vivo imaging, and molecular assays to assess immune and signaling responses.

Main Results:

• Salidroside@T-exo restored T-cell effector functions (IFN-γ, GZMB secretion) and inhibited PI3K/AKT/mTOR signaling in T cells.
• Reduced CSC migration, invasion, and stemness markers (OCT4, NANOG, SOX2).
• Inhibited tumor growth, reduced proliferation (Ki-67), decreased CSC frequency, and increased apoptosis (TUNEL).

Conclusions:

• Salidroside@T-exo effectively reverses PD-1 blockade resistance in breast cancer.
• The mechanism involves simultaneous inhibition of PI3K/AKT/mTOR signaling in T cells and eradication of breast CSCs.
• This approach presents a clinically translatable strategy for refractory breast cancer immunotherapy.