Spatiotemporally Ultrasound‐Controlled Nanoparticles Reprogramming Immunostimulatory Antigen‐Presenting Cancer‐Associated Fibroblasts to Enhance Cancer Immunotherapy

ABSTRACT Cancer‐associated fibroblasts (CAFs) are a major component of the tumor microenvironment and represent a potential therapeutic target for fibrotic breast cancer. Myofibroblastic CAFs (myCAFs), the major subtype, form a tumor barrier by generating a dense extracellular matrix (ECM) that greatly limits the penetration of immune cells and promotes an immunosuppressive microenvironment. Reprogramming the immunosuppressed myCAFs into the immune activated antigen presenting CAF (apCAFs), rather than directly eliminating CAFs, is a better treatment modality. We developed a spatiotemporally ultrasound‐controlled nanoparticle (mRNA/V@M NPs) based on a lipid‐polymer hybrid drug delivery platform to co‐encapsulate CD74 mRNA and V‐9302. Interestingly, this study found that successfully reprogrammed myCAFs could activate CD4 ⁺ T cells, reduce the ECM, and promote immune cell infiltration through the CD74‐MHC II pathway. To overcome the limitation of MHC I immunodeficiency, V‐9302 was used to induce immunogenic cell death (ICD) in tumor cells and activate dendritic cells (DCs) to compensate for MHC I‐mediated immunodeficiency. In conclusion, in a fibrotic triple‐negative breast cancer mouse model, mRNA/V@M NPs combined with ultrasound treatment significantly enhanced MHC I and MHC II activation and increased CD8 ⁺ T cell infiltration and suppressed immunosuppressive TME, thereby triggering robust systemic antitumor immunity.