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The role of lifestyle interventions in treatment success has become essential for nearly every disease. Healthy dietary habits, regular exercise, and stress management are key pillars that can improve quality of life during treatment, as well as delay disease onset and progression. In this study, we focus on the combination of mild calorie restriction (CR) and voluntary exercise as coadjuvants to chemotherapy in the treatment of triple-negative breast cancer using the 4T1 mouse model. In this model, voluntary exercise did not add benefits beyond chemotherapy plus CR in terms of primary tumor size, body composition, or physical performance, while dampening the antimetastatic effect of CR in the lungs of sedentary mice. These findings highlight the challenges of translating results from one preclinical model to another, and ultimately to humans. Diet and exercise type and chemotherapeutic agent influence the outcomes of each type of cancer. More research is needed to determine if and when exercise should be recommended to particular cancer patients.