Transforming Tumor Microenvironment: Exosome-Mediated TAM Reprogramming for Enhanced Anti-Tumor Efficacy

Tumor-associated macrophages (TAMs) contribute to a suppressive tumor environment by hindering T cell functions and fostering resistance to immune checkpoint therapies. Traditional approaches to impede TAMs have shown limited success. This study introduces a novel therapeutic strategy using engineered exosomes loaded with antisense oligonucleotides (ASOs) aimed at STAT6 and C/EBPβ, key regulators of TAM immunosuppression. The exosome-based ASOs (exoASOs) are designed to specifically target TAMs, reducing the expression of STAT6 and C/EBPβ, and converting M2-like TAMs into M1-like, pro-inflammatory cells.

The study found that exoASO-STAT6 and exoASO-C/EBPβ effectively downregulated their respective target genes in human M2 macrophages, leading to a significant shift towards an M1 phenotype. Intravenous administration of exoASOs in a tumor-rich model showed selective uptake by myeloid cells and macrophages. Both exoASOs demonstrated efficacy as single agents, with complete response rates of 50% and 60% respectively, outperforming anti-PD1 or anti-CSFR1 monoclonal antibodies, which showed no efficacy.

The combination of exoASO-C/EBPβ with anti-PD1 therapy further enhanced efficacy, achieving an 80% complete response rate and improved survival rates. Notably, mice that achieved complete response with exoASO therapies showed no tumor growth upon re-challenge, indicating durable anti-tumor effects.

In an orthotopic hepatocellular carcinoma model, exoASO-C/EBPβ treatment significantly reduced liver to body weight ratios and tumor lesions, unlike treatments with free ASOs or anti-CSF1R antibodies, which were ineffective.

The findings suggest that exoASO-STAT6 and exoASO-C/EBPβ are potent as monotherapies and that exoASO-C/EBPβ, when combined with checkpoint inhibitors, offers increased therapeutic potential. This represents a pioneering targeted approach against TAMs, offering a new avenue for cancer treatment.