Engineered TIGIT-Blockade Membrane Vesicles Synergize with Microwave Ablation to Mediate Liver Metastases Eradication.

Abstract

Microwave ablation (MWA) represents a highly effective and clinically significant therapeutic modality for the treatment of liver metastases. The proliferation of disseminated tumor cells within the peri-necrotic transition zone (TZ) is a critical factor contributing to the postablative recurrence; to date, no effective method has been identified to specifically target and eliminate these cells. Here, based on an experimental liver metastases model, we leverage single-cell RNA sequencing and flow cytometry analysis, which reveals that TZ exhibits a VEGF-mediated immunosuppressive microenvironment, characterized by a significant increase of CD155myeloid cells. We further report the development of engineered cell membrane vesicles encapsulating Bevacizumab, which are fused with TIGIT-expressing membranes and platelet membranes (referred to as Bev@TPNVs). The Bev@TPNVs can specifically target the liver and the TZ, inhibit neovascularization, and restore the anti-tumor functionality of CD8T cells. Our findings demonstrate that Bev@TPNVs can effectively suppress liver metastasis after MWA. The intrahepatic metastasis burden is reduced by approximately 10-fold compared with the control group, and the survival rate of mice within 70 days reaches 50%. This work has the potential to establish a novel standard treatment paradigm that could revolutionize combined immunotherapy following liver metastasis ablation.