Effects of caloric restriction on immunosurveillance, microbiota and cancer cell phenotype: Possible implications for cancer treatment

Fasting, caloric restriction and foods or compounds mimicking the biological effects of caloric restriction, known as caloric restriction mimetics, have been associated with a lower risk of age-related diseases, including cardiovascular diseases, cancer and cognitive decline, and a longer lifespan. Reduced calorie intake has been shown to stimulate cancer immunosurveillance, reducing the migration of immunosuppressive regulatory T cells towards the tumor bulk. Autophagy stimulation via reduction of lysine acetylation, increased sensitivity to chemoand immunotherapy, along with a reduction of insulin-like growth factor 1 and reactive oxygen species have been described as some of the major effects triggered by caloric restriction. Fasting and caloric restriction have also been shown to beneficially influence gut microbiota composition, modify host metabolism, reduce total cholesterol and triglyceride levels, lower diastolic blood pressure and elevate morning cortisol level, with beneficial modulatory effects on cardiopulmonary fitness, body fat and weight, fatigue and weakness, and general quality of life. Moreover, caloric restriction may reduce the carcinogenic and metastatic potential of cancer stem cells, which are generally considered responsible of tumor formation and relapse. Here, we reviewed in vitro and in vivo studies describing the effects of fasting, caloric restriction and some caloric restriction mimetics on immunosurveillance, gut microbiota, metabolism, and cancer stem cell growth, highlighting the molecular and cellular mechanisms underlying these effects. Additionally, studies on caloric restriction interventions in cancer patients or cancer risk subjects are discussed. Considering the promising effects associated with caloric restriction and caloric restriction mimetics, we think that controlled-randomized large clinical trials are warranted to evaluate the inclusion of these non-pharmacological approaches in clinical practice.