Targeting LGALS1 via CAF‐Derived Extracellular Vesicles Synergizes With αPD‐1 to Reverse Immunosuppression and Sensibilize Chemo‐Immunotherapy for Colorectal Cancer

Colorectal cancer (CRC) exhibits intrinsic resistance to conventional therapeutic regimens. By integrating single‐cell and bulk transcriptomic data from CRC cohorts, we demonstrate that proliferative capacity alone constitutes an inadequate prognostic predictor. Instead, an immunosuppressive tumor microenvironment (TME) emerges as the dominant driver of disease progression. Galectin‐1 (LGALS1), highly upregulated in metastatic CRC, correlates with robust infiltration of regulatory T cells (Tregs) and M2 macrophages to facilitate immune evasion and poor clinical outcomes, thereby serving as a promising therapeutic target for anti‐tumor immunotherapy. The stromal barrier mediated by cancer‐associated fibroblasts (CAFs) restricts intratumoral penetration of antitumor agents and diminishes therapeutic efficacy. To overcome this physical barrier, we constructed a CAF extracellular vesicle‐based co‐delivery platform termed CEV@Comb, encapsulating the LGALS1 inhibitor OTX008 and 5‐fluorouracil (5‐FU). CEV@Comb selectively accumulates in tumors, suppresses growth in vitro and in vivo, and remodels the immunosuppressive TME by boosting M1 macrophages and cytotoxic CD8 + T cells while reducing intratumoral Tregs. Combination therapy with CEV@Comb and anti‑programmed death‑1 antibody (αPD‐1) further amplifies anti‐tumor immunity in the Apc −/− , Kras G12D , Trp53 −/− , Smad4 −/− (AKPS) CRC mouse model. This study identifies LGALS1 as a core immunosuppressive mediator and provides an innovative chemoimmunotherapeutic strategy to improve clinical outcomes for patients with advanced CRC.