A Candidalysin-Neutralizing Nanomodulator Enhances Colorectal Cancer Immunotherapy by Targeting Fungi–Macrophage Crosstalk

In colorectal cancer (CRC), the upregulation of <i>Candida albicans</i> (<i>C. albicans</i>) abundance significantly promotes tumor progression and exacerbates immunosuppression. In this study, we demonstrate that candidalysin-induced macrophage pyroptosis contributes to the immunosuppressive tumor microenvironment (TME). Conversely, the neutralizing peptide of candidalysin, isolated via phage display, effectively protects macrophages from pyroptosis. Based on this, we constructed an epigenetic inhibitor-loaded nanomodulator to target the interaction between <i>C. albicans</i> and macrophages. To ensure precise targeting of intraspecific morphological differences, the nanomodulator is covered with the <i>C. albicans</i> pretreated macrophage membranes. The nanomodulator exhibits the ability to protect macrophages from pyroptosis and reprograms the metabolic and immune response of macrophages, while the epigenetic inhibitor upregulates tumor self-antigen presentation. In vivo, the nanomodulator has been shown to effectively sustain macrophage activation within the TME and promotes a robust IL-17-mediated immune response. Meanwhile, the nanomodulator exhibited excellent immune memory effects and effectively synergized with immune checkpoint blockade therapy in an orthotopic CRC model. This approach of manipulating the <i>C. albicans</i>-macrophage crosstalk to augment therapeutic efficacy in CRC offers promising insights for the clinical management of CRC.