Exercise suppresses breast cancer and reprograms the immune tumor microenvironment, cancer cell intrinsic features, and their interaction

Exercise links with improved cancer outcomes following a diagnosis of primary breast cancer but experimental evidence from preclinical studies and molecular mechanistic insights are limited. Here, we show that exercise inhibits breast cancer growth and metastases across multiple syngeneic mouse models compared to sham control. Utilizing the Met1-iRFP model to interrogate tumor microenvironmental (TME) and tumor-specific effects, exercise decreased intratumoral immune cell content, particularly tumor-associated macrophages, and prompted an activated anticancer innate immune response. Cancer cell-intrinsic effects were characterized by broad transcriptomic reprogramming including downregulation of metabolic pathways and upregulation of pathways regulating proliferation and apoptosis. Metabolomic analyses unveiled broad shifts in tumor metabolism including decreased NAD+ and lactate, as well as availability of biosynthetic precursors. Finally, in silico analyses identified TME ligands such as Hmgb2 as drivers of downstream gene expression changes in cancer cells. Collectively, our findings show that exercise suppresses breast cancer progression and does so via broad reprogramming of TME-cancer components and their interaction.