Cancer is a major public health issue worldwide. Lifestyle factors, such as body weight and physical activity (PA), significantly impact cancer risk and progression. There is strong evidence that PA reduces and obesity increases risk and mortality from numerous cancer types. Energy restriction (ER) in non-obese hosts significantly reduces tumor incidence in a variety of preclinical models, and reduces body weight and cardiometabolic risk factors in humans. Emerging data suggest that PA- and ER-induced changes in inflammatory and immune mediators may contribute to the cancer prevention effects of these interventions. A systematic literature search was conducted to identify studies that evaluated the impact of PA and ER on tumor and immune outcomes in humans and animal models. A total of 97 eligible studies were identified (68 studies reporting PA interventions and 30 studies reporting ER interventions). Thirty-one studies investigated the effect of PA on cancer immune outcomes using preclinical cancer models of breast (n=17, 55%), gastrointestinal (n=6, 19%), melanoma (n=4, 13%), and several other cancer types (n=4, 13%). Despite the heterogeneity in study designs, the majority of studies (n=23, 74%) reported positive effects of PA on tumor outcomes. Thirty-seven clinical studies investigated the effect of PA on cancer immune outcomes. None reported tumor outcomes, thus only immune outcomes were evaluated in these studies. PA studies were conducted in patients with breast (n=22, 59%), gastrointestinal (n=5, 14%), prostate (n=2, 5%), esophageal (n=1, 3%), lung (n=1, 3%) cancer, leukemia (n=1, 3%), or mixed cancer types (n=5, 14%). Twenty-two studies investigated the effect of ER interventions on cancer immune outcomes using preclinical cancer models including breast (n=5, 23%), gastrointestinal (n=5, 23%), lung (n=2, 9%), liver (n=2, 9%), pancreatic (n=2, 9%), and several other cancer types (n=6, 27%). Positive effects of ER on tumor outcomes were reported in 21 of 22 studies. Six clinical studies investigated the effect of ER (in combination with PA) on tumor immune outcomes in cancer patients with overweight or obesity. Five were conducted in breast cancer patients, and one recruited patients of a mix of cancer types. A wide range of immunological parameters including immune cell phenotype and function, cytokines, and other immune and inflammatory markers were assessed in multiple tissue compartments (blood, spleen, lymph nodes and tumor) in the included studies. Results from preclinical and clinical studies suggest that both PA and ER exert heterogeneous effects on circulating factors and systemic immune responses. PA + ER alters the gene expression profile and immune infiltrates in the tumor which may result in a reduction in immune suppressive factors. However, additional studies are needed to better understand the effect of PA and/or ER on immunomodulation, particularly in the tumor microenvironment (TME).