The role and its mechanism of intermittent fasting in tumors: friend or foe?

Abstract

Intermittent fasting (IF) is becoming a prevailing topic worldwide, as it can cause changes in the body's energy metabolism processes, improve health, and affect the progression of many diseases, particularly in the circumstance of oncology. Recent research has shown that IF can alter the energy metabolism of tumor cells, thereby inhibiting tumor growth and improving antitumor immune responses. Furthermore, IF can increase cancer sensitivity to chemotherapy and radiotherapy and reduce the side effects of these traditional anticancer treatments. IF is therefore emerging as a promising approach to clinical cancer treatment. However, the balance between long-term benefits of IF compared with the harm from insufficient caloric intake is not well understood. In this article, we review the role of IF in tumorigenesis and tumor therapy, and discuss some scientific problems that remain to be clarified, which might provide some assistance in the application of IF in clinical tumor therapy.

Keywords: Intermittent fasting; energy metabolism; immune escape; immunotherapy; tumor.

Figure 1

Overview of the major progression of intermittent fasting research.

Figure 2

The effect of different periods of intermittent fasting (IF). In the early stage of IF, the effect of IF mainly occurs through ketogenesis, which manifests as increased ketone body production, autophagy, and DNA repair, as well as enhanced anti-stress abilities and antioxidant defense. During periods of recovery (including eating and sleeping), the main energy sources of cells are converted from ketones to glucose, which leads to increased glucose, mTOR expression, and mitochondrial biogenesis, enhanced ability to synthesize intracellular proteins, and remodeled growth and functions. During the long-term adaptation period, the insulin sensitivity of cells and body resistance to stress are increased, blood glucose homeostasis and lipid metabolism are further improved, and abdominal fat and inflammation are reduced.

Figure 3

The molecular mechanism by which intermittent fasting (IF) affects tumor cell growth. Mechanistically, IF inhibits the IGF-1/AKT and mTORC1 pathways in tumor cells, while the AMPK, SIRT1, and SIRT3 pathways are activated. In addition, AMPK and SIRTs depend on each other in IF-associated metabolic adaptation. However, AMPK can induce activation of SIRT1 through NAMPT, while SIRT1 can activate AMPK through LKB1 regulation. FOXO3a (a downstream molecule of SIRT1 and SIRT3) and AMPK can each enhance the other’s transcriptional activities. Furthermore, SIRT3 inhibits tumor growth by activating FOXO3a and the expression of superoxide dismutase (SOD), thereby reducing the level of reactive oxygen species and negatively regulating the expression of HIF-1α. SIRT3 activates SOD2 via upregulation of FOXO3a. Furthermore, IF can selectively inhibit tumor growth by upregulating LEPR and its downstream signaling pathway protein, PRDM1.

Figure 4

The effect of intermittent fasting (IF) on tumor immune responses. (A) Under normal conditions, the low autophagy level of tumor cells promotes the expression of CD73 and adenosine, which in turn affects the M2 polarization of tumor-associated macrophages (TAMs). Moreover, the CD39 expression and extracellular ATP increase, which stimulate Tregs and inhibit the functions of cytotoxic T lymphocytes (CTLs). In addition, heme oxygenase 1 is highly expressed in tumors and can inhibit apoptosis and immunostimulatory effects. The lactic acid produced by tumor glycolysis inhibits the function of natural killer (NK) cells. (B) During IF, programmed cell death of tumor cells increases via autophagy and then reduces the expression of CD73 and adenosine in the tumor microenvironment, which inhibits the M2 polarization of TAMs. Furthermore, the expression of CD39 in tumor cells and the accumulation of extracellular ATP are inhibited, thus inhibiting the function of regulatory T cells and stimulating the function of CTLs. Moreover, IF can reduce the lactic acid level, thereby restoring the function of NK cells. Activation of the energy effectors AMPK and PPAR-α (a downstream molecule of AMPK) inhibit the production of CCL2, thereby reducing the migration of monocytes from the bone marrow into the tumor microenvironment.

Figure 5

A diagram of future intermittent fasting issues.