Metastasis to the liver is a major cause of morbidity and mortality associated with a wide range of cancers, including gastrointestinal (GI) malignancies such as pancreatic ductal adenocarcinoma (PDAC). Immunotherapy, whose aim is to harness the body’s own immune system to fight cancer, has recently demonstrated considerable efficacy for patients with a variety of cancer types, including patients with metastatic disease. However, outcomes vary tremendously among different patients, and positive effects often do not last very long. In gastrointestinal malignancies, for instance, metastasis to the liver is common and associated with poor responsiveness to immunotherapy. In pancreatic cancer, which is predicted to become the second-leading cause of cancer-related deaths by 2030, the liver is directly exposed via the portal vein to soluble factors and antigens released by developing tumors. Preliminary work from the Beatty lab has found that the immune microenvironment in the liver is conditioned early during pancreatic cancer development. This results in a liver that displays enhanced susceptibility to metastasis. Based on these findings, Beatty hypothesizes that the immune microenvironment in the liver is inherently malleable; it has the capacity to support or suppress antitumor immunity. During cancer development, the microenvironment is induced to favor cancer cell metastasis and limit the efficacy of cancer immunotherapy. With this grant, Beatty is testing this idea and trying to better understand the exact mechanism by which the liver may regulate the efficacy of immunotherapy. By delineating the underlying mechanisms that generate a “pro-metastatic,” immunotherapy–resistant immune microenvironment within the liver, this work has the potential to provide novel opportunities for clinical intervention and to impact the lives of many patients.