This study is a multicenter, randomized controlled trial. The plan is to enroll eligible participants and randomly assign them to two groups: one group will undergo testing using a combined model of "multi-target blood methylation + fecal FIT + fecal calpetin"; those with positive results will immediately undergo standard gastrointestinal endoscopy, while those with negative results will enter routine observation; the other group will undergo only routine observation and follow-up. All enrolled participants will undergo a 5-year prospective follow-up, during which information on gastrointestinal cancer incidence and mortality will be collected through regular contact and review of medical records. The primary endpoint of the study is the difference in 5-year all-gastrointestinal cancer mortality between the two groups.This project aims to use a randomized controlled trial design to evaluate whether an active screening strategy based on a combined model can effectively reduce the population-level mortality from gastrointestinal cancers compared to routine surveillance. The objective is to provide high-level evidence for establishing a new screening strategy that reduces the disease burden and delivers public health benefits. It lays the foundation for validating novel biomarkers and exploring the biological and behavioral factors that influence screening outcomes, and offers clear decision-making support for optimizing China's comprehensive prevention and control system for gastrointestinal cancers.

Inclusion Criteria:

• 1) Participants must be between 45 and 74 years of age at the time of enrollment; 2) Participants must agree to be randomly assigned to different screening and follow-up strategies; 3) Participants must agree to undergo a five-year follow-up in accordance with the protocol; 4) Participants must be willing to participate and sign an informed consent form.

Exclusion Criteria:

• 1) Underwent upper gastrointestinal endoscopy screening within the past year; 2) History of any type of malignant tumor; 3) Concurrent severe medical conditions that reduce the benefits of screening, such as severe pulmonary disease, kidney disease, liver disease, cardiovascular and cerebrovascular diseases, and hematological disorders; 4) Other situations where a physician determines that endoscopic screening poses excessive risk (e.g., hemodynamic instability) or offers no benefit (e.g., short life expectancy); 5) Pregnant or breastfeeding women.

Applications shall be submitted to the principal investigator upon study completion. Applicants are required to provide a data analysis plan, and data sharing will be approved after assessment.