Engineered MAC-PNV nanovesicles activate T cells and repolarize TAMs, enhancing tumor immunotherapy in mouse models.

The tumor microenvironment (TME) often features an abundance of tumor-associated macrophages (TAMs), particularly the immunosuppressive M2 phenotype, which promotes tumor progression, angiogenesis, and therapeutic resistance. This creates an immunologically "cold" environment, limiting cytotoxic immune cell infiltration and hindering effective cancer therapies. Current standard-of-care treatments often struggle to overcome this immunosuppression. Developing strategies that can both activate anti-tumor immunity and remodel the TME by repolarizing TAMs is a critical gap in cancer immunotherapy.

Researchers developed engineered macrophage-derived nanovesicles (MAC-PNV) from activated DC-like M1 macrophages. These M1 macrophages were reprogrammed using transcription factors PU.1, IRF8, and BATF3, then further stimulated with antigenic peptide, lipopolysaccharide (LPS), and interferon-γ (IFN-γ). In vitro studies assessed CD8+ T cell activation and M2 macrophage repolarization. For in vivo evaluation, MAC-PNV were administered peritumorally to B16-OVA-bearing mouse models to assess tumor growth inhibition and immune cell infiltration. A combination strategy was tested in B16-F10-bearing mouse models, where MAC-PNV were combined with low-dose liposomal doxorubicin (DOX-Lipo, 1 mg/kg), with tumor growth and toxicity as primary endpoints.

The engineered MAC-PNV displayed enriched antigen-presenting complexes and co-stimulatory molecules on their surface. In vitro results demonstrated that these nanovesicles enabled significant activation of CD8+ T cells and effectively repolarized M2 macrophages towards the M1 phenotype. Following peritumoral administration, MAC-PNV alone significantly inhibited tumor growth in B16-OVA-bearing mouse models. This inhibition was attributed to promoting the activation and intra-tumoral infiltration of CD8+ T cells and remodeling the immunosuppressive tumor microenvironment (TME).