Tumor Microenvironment Responsive CD8+ T Cells and Myeloid‐Derived Suppressor Cells to Trigger CD73 Inhibitor AB680‐Based Synergistic Therapy for Pancreatic Cancer

CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti‐PD‐1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8+ T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid‐derived suppressor cells (MDSCs) by tumor‐derived CXCL5 in an AMP‐dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD‐1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8+ T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD‐1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC. The selective inhibitor of CD73, AB680, increases the infiltration of responsive CD8+ T cells by decreasing immunosuppressive adenosine level. AB680 also promotes the myeloid‐derived suppressor cell (MDSC) chemotaxis via tumor‐derived CXCL5 in an AMP‐dependent manner. Targeting the CXCL5/CXCR2 pathway with the CXCR2 inhibitor SB‐225002 disrupts the “side effect” of AB680 and potentiates the efficacy of AB680 plus anti‐PD‐1 therapy.