PROJECT SUMMARY Overview: 1.8 million people die of lung cancer each year across the globe. Immunotherapy, particularly using immune checkpoint inhibitors (ICIs), has revolutionized lung cancer treatments over the last years projecting a significant improvement in cancer prognosis; however, response rates of ICIs are only 15-25%, which is in part due to the lower levels of functional immune cells and insufficient infiltration of immune cells into the tumor. Furthermore, about 70% of patients with NSCLC receiving ICIs experience immunotherapy-related adverse events (irAEs) (e.g., metabolic dysregulation, myalgia, and cardiopulmonary disease). An effective intervention that can enhance treatment responses as well as ameliorate irAEs would be a significant advance in clinical care for patients with NSCLC on ICIs. Exercise has been emerging as a novel approach that can enhance response to immunotherapy and reduce irAEs. Exercise can increase the infiltration of neutrophils in the target cells and circulating levels of T cells and NK cells as well as induce tumor angiogenesis in preclinical settings, which has the potential to induce a better response to ICIs and cancer suppression. Furthermore, exercise is proven to be feasible in patients with lung cancer and to increase cardiopulmonary/muscular fitness and metabolic regulation, which also suggests the potential benefits of exercise to reduce irAEs. However, no exercise clinical studies, to date, have been conducted in patients with lung cancer receiving ICIs. Also, it is unclear which exercise prescription, particularly regarding exercise intensity, would yield better immunological and treatment-related outcomes. Therefore, I propose multi-level clinical research where a pilot randomized clinical trial (K99) will explore the preliminary efficacy and mechanisms of different exercise training on immune function, which will inform a larger Phase II trial (R00) to examine the effects of exercise on immunotherapy response rate and irAEs. Research Plan: The K99 study is a three-arm pilot randomized clinical trial that will compare high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT) vs. usual care (UC) to explore the preliminary efficacy of exercise on immune function (Aim 1) and provide a proof-of-concept of the mechanisms by analyzing biomarkers of immune function, exercise-induced cytokines, and cancer progression (Aim 2). These findings will inform the R00 study, which is a two-arm phase II randomized clinical trial to examine the effects of exercise (most efficacious training from K99) on immune function (Aim 3a), tumor biomarkers (Aim 3b), and immunotherapy response and irAEs (Aim 3c). Career Development Plan: The proposed comprehensive and transdisciplinary training, involving coursework, mentorship, research involvement, and seminars/meetings, will enable me to (1) obtain the fundamental expertise necessary to comprehend the roles of exercise in lung cancer im...