Abstract
The therapeutic potential of chimeric antigen receptor (CAR) T-cell therapy in treating solid tumors is highly recognized, yet the complex and immunosuppressive nature of the tumor microenvironment, poor accessibility, and the instability of target antigens pose substantial challenges. Here, we present an mRNA-LNP-based therapeutic strategy that delivers mRNA encoding a fibroblast activation protein (FAP)-specific CAR to reprogram host immune cells in vivo and target cancer-associated fibroblasts within the tumor stroma. In multiple solid tumor mouse models, this approach, combined with chemotherapeutic agents and immune checkpoint inhibitors, achieved significant tumor regression and induced durable, antigen-specific immune memory. Incorporation of m6A-modified CAR mRNA accelerated and amplified antitumor responses, while blockade of the macrophage migration inhibitory factor (MIF)-CD74 axis further improved tumor control by alleviating immune suppression. In patient-derived xenograft models, HOX family transcription factors were implicated in treatment resistance, highlighting a potential biomarker and therapeutic target. The evidence from this study demonstrates that targeting the tumor microenvironment with a controllable mRNA-modulated strategy achieves substantial antitumor efficacy and holds significant potential to enhance the applicability and acceptance of CAR-T cell therapy across a variety of cancers.