Autotaxin (ATX)-lysophosphatidic acid (LPA) signaling suppresses the accumulation of eosinophils in the pancreatic ductal adenocarcinoma (PDAC) microenvironment, thereby promoting tumor progression. ATX, a secreted enzyme, hydrolyzes lysophosphatidylcholine to generate LPA, which supports tumor growth in various cancers, including PDAC. This study shows that ATX suppresses eosinophil accumulation via an autocrine feedback loop, where ATX-LPA signaling negatively regulates the activity of the AP-1 transcription factor c-Jun, thereby suppressing the expression of the eosinophil chemoattractant CCL11. Eosinophils were identified in human PDAC specimens, and individuals with high intratumor eosinophil abundance had the longest overall survival. These findings, along with previous studies, highlight the context-dependent immune-modulatory potential of ATX-LPA signaling in cancer. The PDAC microenvironment is complex, with immune suppression and poor prognosis associated with the exclusion of leukocyte populations such as T cells and dendritic cells. In contrast, PDAC recruits myeloid cells that can be either tumor-promoting or tumor-suppressive. Eosinophils, which are typically associated with immune responses, have shown antitumor potential in other solid tumors, prompting their investigation in PDAC. ATX signaling promotes PDAC progression by increasing tumor growth and reducing apoptosis, while inhibiting ATX increases eosinophil abundance, which suppresses tumor progression. ATX inhibition also reduces AKT activation in vivo, consistent with previous findings. ATX signaling limits intratumor eosinophil abundance by suppressing CCL11 expression, which is a potent eosinophil chemoattractant. Inhibition of ATX increases CCL11 expression, leading to increased eosinophil recruitment and tumor growth. Conversely, restoring ATX expression reduces eosinophil infiltration and tumor growth. These findings suggest that ATX negatively regulates eosinophil abundance and function in the PDAC microenvironment. The study also shows that ATX disrupts AP-1 activity and CCL11 expression, which is crucial for eosinophil recruitment and tumor progression. These results indicate that ATX negatively regulates AP-1-mediated CCL11 expression in PDAC cells, suppressing eosinophil recruitment into the tumor microenvironment. The findings highlight the potential of ATX as a therapeutic target in PDAC, with implications for combination therapies targeting immune modulation.Autotaxin (ATX)-lysophosphatidic acid (LPA) signaling suppresses the accumulation of eosinophils in the pancreatic ductal adenocarcinoma (PDAC) microenvironment, thereby promoting tumor progression. ATX, a secreted enzyme, hydrolyzes lysophosphatidylcholine to generate LPA, which supports tumor growth in various cancers, including PDAC. This study shows that ATX suppresses eosinophil accumulation via an autocrine feedback loop, where ATX-LPA signaling negatively regulates the activity of the AP-1 transcription factor c-Jun, thereby suppressing the expression of the eosinophil chemoattractant CCL11. Eosinophils were identified in human PDAC specimens, and individuals with high intratumor eosinophil abundance had the longest overall survival. These findings, along with previous studies, highlight the context-dependent immune-modulatory potential of ATX-LPA signaling in cancer. The PDAC microenvironment is complex, with immune suppression and poor prognosis associated with the exclusion of leukocyte populations such as T cells and dendritic cells. In contrast, PDAC recruits myeloid cells that can be either tumor-promoting or tumor-suppressive. Eosinophils, which are typically associated with immune responses, have shown antitumor potential in other solid tumors, prompting their investigation in PDAC. ATX signaling promotes PDAC progression by increasing tumor growth and reducing apoptosis, while inhibiting ATX increases eosinophil abundance, which suppresses tumor progression. ATX inhibition also reduces AKT activation in vivo, consistent with previous findings. ATX signaling limits intratumor eosinophil abundance by suppressing CCL11 expression, which is a potent eosinophil chemoattractant. Inhibition of ATX increases CCL11 expression, leading to increased eosinophil recruitment and tumor growth. Conversely, restoring ATX expression reduces eosinophil infiltration and tumor growth. These findings suggest that ATX negatively regulates eosinophil abundance and function in the PDAC microenvironment. The study also shows that ATX disrupts AP-1 activity and CCL11 expression, which is crucial for eosinophil recruitment and tumor progression. These results indicate that ATX negatively regulates AP-1-mediated CCL11 expression in PDAC cells, suppressing eosinophil recruitment into the tumor microenvironment. The findings highlight the potential of ATX as a therapeutic target in PDAC, with implications for combination therapies targeting immune modulation.