Background: Lung cancer is the most common cause of cancer-related deaths in the United States, with tobacco smoking being the most important risk factor. However, ~60% of individuals at a high risk for lung cancer or with early-stage lung cancer are either overweight or obese. Preliminary studies suggest that the diabetes drug metformin improves survival in high BMI lung cancer patients and inhibits lung cancer progression in preclinical models, likely through its effects on the obesity-triggered changes to the immune microenvironment of the lung, particularly, the regulatory T cells (Tregs) in the airway. Given the known dysregulation of Tregs in obesity and the importance of Tregs in lung carcinogenesis, we hypothesize that metformin therapy will reprogram the immune defense of obesity in directions that are consistent with the control of nascent lung tumor development. While more generalized lung cancer prevention approaches have to date shown limited effectiveness, the targeting of a specific subset of individuals at high risk for lung cancer provides a precision prevention approach, which is likely to be more effective. Methods: This is an open-label, randomized, wait-list control trial, where 50 non-diabetic obese/overweight former smokers with over 20 pack year smoking history and PLCOm2012 Lung Cancer Risk Prediction score above 1.34% will be enrolled. They will be equally randomized to either oral metformin or no treatment for 26 weeks followed by partial crossover, whereby no-treatment subjects will receive metformin for 26 weeks. The open-label, wait-list control design allows inclusion of a control group to assess stability of the primary biomarker in an untreated population while retaining the statistical power of 40 metformin-treated subjects (assuming 20% subject attrition) and will aid accrual since all trial participants will be treated. Treatment regimen is one daily dose of metformin at 500 mg for 1 week followed by 1000 mg for the second week and 2000 mg thereafter for a total of 24 weeks. Sampling for endpoint assessment include bronchoscopy with biopsy and bronchoalveolar lavage (BAL) and blood collection before and after completion of metformin treatment. The primary endpoint is to evaluate the effect of metformin treatment on the expression of PD-1, an immune checkpoint factor, on BAL Tregs. The secondary endpoints include stability of BAL Treg PD-1 expression over time and the impact of metformin on circulating immune cells. Trial sites include Roswell Park Comprehensive Cancer Center, the Rocky Mountain Regional Veterans Affairs Medical Center, and University of British Columbia, Vancouver. Since the trial opened to accrual in March 2022, 77 patients have been pre-screened and 19 were consented. Among them, 10 participants have been enrolled and randomized, 5 in each arm. We expect to complete accrual by April 2024. Clinical trial information: NCT04931017.