Enhanced tumor immunotherapy by nanovesicles derived from engineered DC-like M1 macrophage

Area of Science:

• Biotechnology
• Immunotherapy
• Nanomedicine

Background:

• Tumor-associated macrophages (TAMs) create an immunosuppressive tumor microenvironment (TME).
• Activating cytotoxic CD8+ T cells is crucial for effective anti-tumor immunity.
• Developing novel therapeutics that can simultaneously target TAMs and T cells is needed.

Purpose of the Study:

• To engineer macrophage-derived nanovesicles (MAC-PNV) with dual functions.
• To investigate the ability of MAC-PNV to activate CD8+ T cells and remodel TAMs.
• To evaluate the therapeutic potential of MAC-PNV in preclinical cancer models.

Main Methods:

• Macrophages were reprogrammed using transcription factors PIB (PU.1, IRF8, and BATF3).
• Reprogrammed macrophages were stimulated with antigenic peptide, LPS, and IFN-γ to derive MAC-PNV.
• In vitro assays assessed T cell activation and macrophage repolarization.
• In vivo studies evaluated tumor growth inhibition and combination therapy efficacy in mouse models.

Main Results:

• MAC-PNV exhibited enriched antigen-presenting complexes and co-stimulatory molecules on their surface.
• In vitro, MAC-PNV significantly activated CD8+ T cells and repolarized M2 macrophages to M1 phenotype.
• Peritumoral administration of MAC-PNV inhibited tumor growth by enhancing CD8+ T cell activity and remodeling the TME.
• MAC-PNV significantly improved the anti-tumor efficacy of low-dose doxorubicin and reduced its toxicities.

Conclusions:

• Engineered MAC-PNV possess dual immunomodulatory functions.
• MAC-PNV demonstrate potential as a monotherapy for cancer treatment.
• MAC-PNV can serve as an effective immunomodulatory enhancer for combination therapy with chemotherapeutics.