Remodeling the Inflammatory and Immunosuppressive Tumor Microenvironment for Enhancing Antiangiogenic Gene Therapy of Colorectal Cancer

Abstract

Fusobacterium nucleatum (Fn), as an intestinal pathogenic bacterium, is closely related to the occurrence, progression, and limited therapeutic efficacy of colorectal cancer (CRC). The presence of Fn within CRC communities induces an inflammatory and immunosuppressive microenvironment while promoting new vessel formation. Therefore, developing novel methods to efficiently eliminate Fn and enhance the therapeutic outcomes against Fn-associated CRC is of great significance. Herein, a nanosystem named AFGTs-PEG, which integrates antimicrobial agent lauric acid (LA), an antiangiogenic gene (sFlt-1), a targeted polymer (OEI-LA/PBA, OLP), and DSPE-mPEG, to boost the gene therapy of Fn-infected CRC, is developed. The sFlt-1 gene is delivered to CRC cells through lysosome escape, remarkably inhibiting new vessel formation at the CRC site and ultimately leading to CRC cell death. In principle, LA is used to eliminate Fn and its biofilms, and remodel the inflammatory and immunosuppressive microenvironment by restraining the generation of inflammatory factors and preventing polarization of M1 into M2 macrophages, thereby mitigating the adverse effects of Fn on antiangiogenic gene therapy. This study holds great promise for the treatment of bacteria-colonized tumors.