Cellular Starvation as a Strategy in Cancer Cell Treatment: Mechanisms, Evidence, and Therapeutic Implications

Abstract

Cellular starvation is a cancer therapeutic strategy based on the premise that nutrient deprivation can differentially affect cancer cell survival. Nutrient deprivation encompasses a variety of modalities such as systemic dietary restrictions in fasting and caloric restrictions, pharmacological nutrient starvation mimics, and specific nutrient-depleting compounds. Nutrient deprivation can target key nutrients including glucose, amino acids, and fatty acids. Cancer cells often exhibit heightened reliance on specific nutrients or nutrient classes, and such nutrient dependencies, termed “metabolic addictions”, represent viable opportunities for targeted therapeutic approaches. Cancer metabolic alterations are not only involved in driving malignant transformation but are also dictated by the tumor microenvironment and further shape the tumor-immune microenvironment. Furthermore, metabolic rewiring of cancer cells and cancer-stroma interactions have been shown to modulate redox balance, enhance antioxidant capacity, and impact cellular responses to oxidative and other stresses.

Metabolites derived from glucose, glutamine, fatty acids, and other classes of biomolecules serve as building blocks to sustain the rapid growth and proliferation of cancer cells. Cellular metabolism, especially glucose and lipid metabolism, is tightly coupled to the tumor microenvironment and actively shapes the tumor-immune landscape. Therefore, targeting cancer metabolism and the interconnectedness of cancer cells with the tumor microenvironment holds substantial therapeutic promise.

Distinct cancer cell types carry out remarkably different metabolic rewiring programs during tumorigenesis and adapt diverse strategies to survive under adverse microenvironments. Nutrient deprivation therapy has the capacity to hamper tumor growth and overcome chemoresistance synergistically when combined with chemotherapeutics.

Keywords: Cellular starvation, Cancer, Cancer treatment, Free treatment, Cell therapy.