Stratifying nutritional restriction in cancer therapy: Next stop, personalized medicine

Dietary interventions combined with cancer drugs represent a clinically valid polytherapy. In particular nutrient restriction (NR) in the form of varied fasting or caloric restriction regimens holds great clinical promise, conceptually due to the voracious anabolic appetite of cancer cells. This metabolic dependency is driven by a strong selective pressure to increasingly acquire biomass of a proliferating tumor and can be therapeutically exploited as vulnerability. A host of preclinical data suggest that NR can potentiate the efficacy of, or alleviate resistance to, cancer drugs. However, complicating clinical implementation are the many variables involved, such as host biology, cancer stage and type, oncogenic mutation landscape, tumor heterogeneity, variations in treatment modalities, and patient compliance to NR protocols. This calls for systematic preclinical screens and co-clinical studies to predict effective combinations of NR with cancer drugs and to allow for patient stratification regarding responsiveness to polytherapy. Such screen-and-stratify pipelines should consider tumor heterogeneity as well as the role of immune effectors in the tumor microenvironment and may lead to biomarker discovery advancing the oncology field toward personalized options with improved translatability to clinical settings. This opinion-based review provides a critical overview of recent literature investigating NR for cancer treatment, pinpoints limitations of current studies, and suggests standardizations and refinements for future studies and trials. The proposed measures aim to increase the translational value of preclinical data and effectively harness the vast potential of NR as adjuvant for cancer therapy.