Clinical and epidemiologic studies have demonstrated that exercise reduces the incidence and improves the
prognosis of numerous types of cancer; however, the mechanisms by which exercise exerts its anti-cancer
effects remain poorly understood. Most exercise studies have been performed in breast cancer; however, as
breast cancer is obesity-associated, insulin-driven, and only weakly immunogenic, it is likely that exercise may
work differently in cancer types that are strongly immunogenic and not associated with obesity. A mechanistic
understanding of how exercise slows tumor growth is important because it will inform the design of clinical trials
to determine which exercise regimens are most likely to benefit a particular tumor type based on a patient's
clinical characteristics, allowing an exercise prescription to be made using precision medicine approaches.
Arguably more importantly, studies in this vein may reveal new therapeutic targets for lung cancer by modulating
metabolism in combination with standard-of-care treatments. In this proposal, we will examine how exercise
slows lung cancer growth in mice, with the Overarching Hypothesis that the beneficial effects of exercise on
lung cancer progression result from a combination of systemic metabolic interactions linking muscle to the
immune system to the tumor. We anticipate that exercise both reduces tumor glucose uptake, and increases
immune cell glucose and fatty acid metabolism, thereby enhancing T cell activation, and preventing exhaustion.
These hypotheses will be tested using a complement of tissue-specific knockout mice, methods that we
developed to model tissue-specific substrate metabolism, and multiple exercise modalities mimicking low-
intensity exercise as well as high-intensity interval training. In so doing, we anticipate generating new insights
into how muscle-tumor-T cell interactions mediate the beneficial effects of exercise in immunogenic tumors, and
may identify new immunometabolic targets to enhance the efficacy of exercise, generating an evidence-based
exercise prescription for lung cancer in mice.