Unhealthful lifestyle factors, such as obesity, disrupt organismal homeostasis and accelerate cancer pathogenesis, partly through metabolic and immunological dysregulation. Exercise is a prototypical strategy that maintains and restores homeostasis at the organismal, tissue, cellular and molecular levels and can prevent or inhibit numerous disease conditions, including cancer. Here, we review unhealthful lifestyle factors that contribute to metabolic and immunological dysregulation and drive tumourigenesis, focusing on patient physiology (host)-tissue-tumour microenvironment interactions. We also discuss how exercise may influence distant tissue microenvironments, thereby improving tissue function through both metabolic and immunospecific pathways. Finally, we consider future directions that merit consideration in basic and clinical translational exercise studies.