Hepatobiliary malignancies represent a major cause of mortality globally and are uniquely aggressive in Latin America. The most common tumors are: hepatocellular carcinoma (HCC) affecting young individuals in Latin America and being the second most common cause of cancer-related death worldwide; cholangiocarcinoma (CCA) with minimal survival upon diagnosis and largely understudied in the region; gallbladder cancer (GBC) being a rare tumor worldwide but representing the second most common cause of cancer-related death in women in Chile. Key factors related to the excessive mortality of these tumors are the lack of reliable screening methods and the complexity of diagnosis, which requires advanced imaging technology and difficult-to-access tissue. These barriers are amplified by poor accessibility present in resource-limited regions, all of which leads to tumors being diagnosed at advanced stages in which curative therapy is not an option. To overcome these barriers, we propose to: A) validate immune-related markers in serum to predict HCC in South America and evaluate factors associated to early HCC development; B) define the utility of extracellular vesicles in serum as biomarkers for diagnosis of CCA and determine genetic and infectious factors that increase risk for this cancer; and C) identify biomarkers for GBC detection and evaluate novel immune factors that affect the geographical impact of this tumor. This project advances the field by focusing on a unique approach to screen and diagnose tumors based on serum detection of biomarkers before a tumor is visible on imaging, allowing for early tumor detection in a cost effective manner that will lead to implementation of curative therapies. In addition, this project addresses modifiable risk factors for hepatobiliary tumors that could be targeted for prevention. This project will result in novel tools that are easily accessible and will dramatically reduce the burden of cancer-related mortality in Latin America.