Amelioration of colorectal cancer-associated fibroblasts in immunosuppressive microenvironment by ferroptosis-based nanotherapy

Abstract

Most colorectal cancers (CRCs) are insensitive to cancer immunotherapy due to the tumor-promoting activities and immunosuppressive effects of cancer-associated fibroblasts (CAFs), which profoundly drive cancer progression. Here, we provide a treatment strategy targeting CAFs to remodel the structural and immune tumor microenvironment of CRC based on magnetic nanoparticles. These nanoparticles not only induce the enhanced ferroptosis of CAFs through the synergistic effect of iron and copper ions but also ameliorate the immunosuppressive tumor microenvironment, simultaneously breaking down physical obstructions and activating the immune system. Mechanistically, these nanoparticles regulate the intrinsic signaling pathways of CAFs and alter chemokine secretion to improve the maturation of dendritic cells and the activation and function of CD8⁺ T cells, eventually resulting in boosting the immune response to inhibit CRC growth. Moreover, we verify the effectiveness of this strategy in the patient-derived xenograft and organoid models, further illustrating its universality and promising clinical translational potential. Collectively, we show that our magnetic nanoparticles targeting CAFs can reprogram the tumor microenvironment of CRC by breaking down physical barriers and alleviating immunosuppression, offering promising avenues for the therapeutic strategy in clinical CRC management.