The Effects of Dietary on Tumor Metabolism: History
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Subjects: Immunology
Contributor:
Salvatore Cortellino
,
Valter D. Longo

The remodeled cancer cell metabolism affects the tumor microenvironment and promotes an immunosuppressive state by changing the levels of macro- and micronutrients and by releasing hormones and cytokines that recruit immunosuppressive immune cells. Novel dietary interventions such as amino acid restriction and periodic fasting mimicking diets can prevent or dampen the formation of an immunosuppressive microenvironment by acting systemically on the release of hormones and growth factors, inhibiting the release of proinflammatory cytokines, and remodeling the tumor vasculature and extracellular matrix.

  • diets
  • metabolism
  • cancer

1. Introduction

The effectiveness of anti-tumor therapies is determined by cancer cell-intrinsic factors such as the genomic landscape and cell signaling, as well as by the connective tissue, vessels, fibroblasts, and immune cell infiltration that compose the tumor microenvironment (TME) and contribute to the generation of immunosuppressive environment and immune evasion [1][2][3].
Tumor cells determine TME cell composition through the release of chemokines and cytokines that attract certain cell populations and manipulate TME cell function and differentiation through direct cell–cell interactions or through the release of growth factors, cytokine, and metabolic byproducts.
In recent decades, cancer metabolism has emerged to play an essential role in shaping the TME composition and the properties and functions of its constituents [4]. Dietary interventions such as calorie restriction (CR), fasting, and fasting mimicking diets (FMD) have received much attention as several preclinical and clinical studies have shown their efficacy in modulating tumor metabolism, remodeling the tumor microenvironment, and even enhancing the antitumor immune response [5][6][7][8][9][10][11].

2. Effects of Fasting and Metabolite Restriction on Cancer Cells

Food restriction induces systemic and local metabolic changes through the modulation of hormone and nutrient sensing pathways. The reduction of circulating glucose upon dietary restrictions leads initially to glycogenolysis in order to support gluconeogenesis; then, when glycogen storage is depleted, it leads to lipolysis and the release of glycerol and fatty acids essential for the production of ketone bodies, the main energy sources in the absence of external nutrients [8][12]. The organism responds to the macronutrients and particularly amino acid limitation by inhibiting the anabolic pathways through the downregulation of growth hormone (GH) and insulin growth factor (IGF1). The low level of IGF 1 and of amino acid and increased AMP/ATP ratio lead to the inhibition of PI3K and mTOR pathway and to the activation of autophagy, a process that provides energy and substrates by removing the damaged and redundant self-components [13][14].
In normal cells, the effects of CR on the reduction of growth factors is also associated with the upregulation of anti-stress response (NRF2 and antioxidant genes), which can include DNA repair and cause reduced inflammation trough the release of corticosteroids, ghrelin, and adiponectin and the inhibition of pro-inflammatory cytokine secretion [15][16].
The inhibition of the nutrient-sensing pathway (IGF1-PI3K-mTOR), the activation of the antistress response pathway, and the upregulation of genes involved in DNA repair induced by caloric restriction/fasting prompt normal but not cancer cells to slow down their proliferation and enter a quiescent state, an effect called “differential stress resistance” which protects normal but not malignant cells from the cytotoxicity of anti-tumor drugs. However, tumor cells that possess mutations in oncogenes (IGF-1R, Ras, AKT, and mTOR pathways) and tumor suppressor genes (p53, p16, and Rb) are not only insensitive to lack of nutrients and low levels of anabolic hormones and do not become protected during fasting condition, their uncontrolled proliferation and increased requirement for many metabolites can sensitizes them to anticancer therapy. This mechanism induced by fasting in tumor cells is termed differential stress sensitization, since only cancer cells (breast, glioma, neuroblastoma, melanoma) and not normal cells are sensitized to a wide variety of therapies ranging from chemotherapy to radiotherapy to hormone therapy (DSS) [17][18][19][20].
A key effect of fasting is the reduction of carbohydrates, which are the main energy source for many types of cancers. The scarcity of carbohydrates has a particular impact on the metabolism of tumor cells, which, prior to the restriction, adopt an increased glycolytic mode, called the Warburg effect, and which, in response to glucose restriction, attempt to shift from glycolysis to oxidative phosphorylation to generate more energy but also as the fatty acids and ketone bodies generated by lipolysis become a fuel source. However, glycolysis-dependent tumor cells (ovarian, breast, thyroid cancer) are unable to effectively adapt their metabolism to OXPHOS, so this change induces a slowdown in proliferation and an increase in oxidative stress and apoptosis [21][22][23].
The energy deficit induced by caloric restriction/fasting leads to an increase in NAD+, which activates histone deacetylase sirtuins. Sirtuins reshape the epigenetic landscape, causing an inhibition of glycolysis and thus reinforcing the inhibitory effect of calorie restriction on tumor glucose metabolism [24][25][26].
Cycles of fasting or fasting-mimicking diets (FMD), developed to simulate the effects of fasting and lasting 2–5 days, also sensitizes glycolysis-dependent cancer cells (TNBC) to glucose analogues (2DG) and affects cancer stem cell self-renewal [27]. Furthermore, the reduction of glucose and circulating IGF enhance the efficacy of cycline kinase inhibitors/hormone therapy combination and PI3 kinase inhibitors against ER-positive and triple-negative tumors, respectively, preventing drug resistance in ER+ breast cancers [28] and completely eradicating triple-negative breast tumors [27].
Fasting cycles could affect tumor growth by modulating the levels of essential (leucine, lysine, and methionine) and non-essential (serine, glycine, glutamine, and asparagine) amino acids [29].
For example, serine deprivation activates the serine synthesis pathway and inhibits glycolysis by promoting OXPHOS [30][31]. This metabolic switch increases ROS production, thus sensitizing colorectal tumors, lacking p53, to agents that increase ROS [32]. Fasting/FMD also alters the iron metabolism in KRAS-mutated tumor (pancreas, lung, colorectal) cells by reducing the levels of heme oxygenase and ferritin, thus increasing sensitization to high doses of vitamin C, which acts as a pro-oxidant agent [33].
Methionine restriction also inhibits tumor growth and increases the efficacy of chemotherapies [34][35] and reverses the drug resistance of RAS-driven colorectal cancer as it affects nucleotide metabolism and glutathione synthesis and reactivates the expression of silent tumor suppressor genes by reshaping the epigenetic and DNA methylation landscape [36].
Several cancer cells are glutamine-addicted because glutamine plays an essential role in cell metabolism as it supplements tricarboxylic acid (TCA) cycle and participates in the biosynthesis of nucleotides, glutathione (GSH), fatty acid, and other nonessential amino acids (alanine, proline, aspartate, asparagine, and arginine) [37]. In addition, glutamine support the production of α-KG, which is a cofactor for Jumonji C domain-containing histone demethylases (JmjC), and ten-eleven translocation (TET) family DNA demethylases [38][39]. Therefore, glutamine deprivation affects cancer growth by impairing the energy and nucleotide metabolism and redox homeostasis [40]. However, glutamine depletion leads to histone and DNA hypermethylation through the inhibition of JmjC and TET. These epigenetic changes promote cancer cells dedifferentiation and drug resistance [41].
Fasting mobilizes lipids from adipose tissue as beta-oxidation of fatty acids becomes the main energy source in glucose deficiency. Therefore, the high consumption of lipids at the cellular level allows for a reduction in plasma lipid levels [8]. This metabolic change affects the metabolism of cancer cells and their ability to adapt. In fact, tumor cells dependent on glycolysis can be more affected by this metabolic change as they are not able to effectively process the fatty acids that accumulate in the lipid droplets [42]. Furthermore, CR reduces the activity of the enzyme stearoyl-CoA desaturase (SCD), essential for maintaining the fluidity of the cytoplasmic membrane through the production of monounsaturated fatty acids (MUFA) [22].
On the contrary, the growth of tumor lines, whose metabolism relies on OXPHOS, is less affected by the effects of caloric restriction and fasting, as they support their growth through the beta oxidation of fatty acids, which are reduced in the tumor microenvironment [42].
Calorie restriction and fasting may exert an antitumor action through downregulation of the satiety hormone leptin and upregulation of adiponectin. Fasting blocks the progression of acute lymphocytic leukemia (ALL) through upregulation of the leptin receptor (LEPR). LEPR expression slows cell proliferation and promotes ALL differentiation by upregulating XBP1, involved in the unfolded protein response (UPR) pathway, and PRDM1, the tumor suppressor gene involved in T and B cell differentiation [43]. Calorie restriction has been shown to prevent the risk of radiation-induced myeloid leukemia in mice if performed both before and after irradiation [44]; however, it has no effect on multiple myeloma progression, although it is able to remodel the microenvironment of the bone marrow [45]. Therefore, the antitumor effects of CR and FMD are cancer specific and dependent on the genotypic and phenotypic characteristics of the tumors.

3. Effects of Fasting and Caloric Restriction on TME

Although the reduction of glucose and essential and non-essential amino acids has a detrimental effect on tumor growth, such restrictions also negatively impact the function of the immune system. Glucose reduction suppresses proliferation and activation of tumor infiltrating effector immune cells while promoting the formation of long term memory CD8+ T cells [46][47]. At the same time, glycine and serine restriction inhibit CD8 T cell activation [48], while low methionine levels impair CD4 T cell activation by reducing histone methylation at the levels of genes involved in T cell proliferation and activation [49].
Although calorie restriction/fasting reduces glucose and amino acids levels, such dietary interventions have been shown to have beneficial effects on the antitumor response by increasing the percentage of CD8+ cytotoxic T cells, memory T cells, and stem cell-like memory T cells and repressing Treg through the reduction of IGF1 levels, epigenetic reprogramming, and the production of ketone bodies [42][50][51][52][53][54][55][56].
More recently, fasting/FMD cycles were shown to promote the immune cell-dependent attack of different types of cancer cells (melanoma, breast, gastric cancers) [41][42][54][57][58].
This was attributed to the ability of fasting/FMD to reduce the Treg population and boost CD8 infiltration by downregulating the expression of heme oxygenase-1 (HO-1) and IGF-1 and by inducing autophagy in melanoma and breast cancer [56][57]. FMD potentiates the cytotoxic effect of chemotherapy and increases the immune infiltrate in breast and melanoma cancer by reducing tumor HO-1 expression, a potent immunomodulator involved in suppressing CD8+ T-cells infiltration and cytotoxic activity and promoting Treg accumulation [57]. Fasting sensitizes low immunogenic non-small-cell lung cancer lung tumors to anti-PD1 immunotherapy and even leads to complete tumor remission in preclinical studies by reversing or neutralizing the immune evasion mechanism through IGF-I signaling pathway downregulation [56].
Since IGF-1 cooperates with the receptor for advanced glycation end products (RAGE) in inducing metabolic-dependent inflammatory responses, and since RAGE activation amplifies IGF-1 signaling, CR and FMD could improve the antitumor immune response by modulating the RAGE signaling pathway. RAGE activation by advanced glycation end-products and 25 other ligands induces transcription of inflammatory cytokines and chemokines that contribute chronic inflammation in the tumor microenvironment promoting MDSC recruitment, TAM polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype, DC dysfunction, and T cell exhaustion. Furthermore, RAGE triggers the activation of the NLRP3 inflammasomes pathway, which favors immunosuppression by promoting the genesis and recruitment of MDSC or by inducing the differentiation of TAMs into a tolerogenic phenotype [59]. CR and FMD suppress inflammation and reduce oxidative damage in humans and in preclinical mouse models [16][60]. Furthermore, FMD reduces the levels of inflammatory markers such as the NLRP3 inflammasome, leukotriene in the heart of mice bearing melanoma and lung cancer and treated with immune checkpoint inhibitors [61][62].
Fasting improves chemotherapy efficacy against fibrosarcomas, mammary carcinomas, and non-small cell lung cancers by boosting the T-cell-mediated immune response, which leads to Treg depletion through enhanced ATP release due to fasting-induced autophagy in the tumor [58].
The effects of calorie restriction and diet on immune system activation could also be mediated through the reduction of high mobility group box protein 1 (HMGB1) [63].
HMGB1 is a multifunctional redox sensitive protein secreted by innate immune system cells (macrophages and NK) in TME under stress or inflammatory conditions. Extracellular HMG1 can play both protumor and antitumor roles. Reduced HMGB1 promotes immune cell activation and chemotaxis by stimulating the synthesis and release of proinflammatory cytokines, such as TNFα and IL1,6, through activation of the receptor for advanced glycation end products (RAGE) and/or Toll-like receptor (TLR) signals 2, 4 [64]. On the other hand, oxidized HMGB1, mostly present in the interstitial fluid of TME, inhibits DC activation and renders them tolerogenic via RAGE activation [65].
In addition to modulating the immune response, HMGB1 inhibits tumor growth and promotes the death of some tumor forms (as colorectal cancer) by inducing a metabolic shift towards anaerobic glycolysis through the inhibition of PKM2, an enzyme involved in the conversion of phosphoenolpyruvate into pyruvate, essential for the fuel of TCA and oxidative phosphorylation [66].
It has recently been shown that inhibition of extracellular HMGB1 blocks the growth of breast tumors through activation of the adaptive immune system and improves efficacy of immune checkpoint therapy (PD-1) by reducing the percentage of Tregs and increasing the percentage of M1 macrophages and activated DCs [67].
Recently it is emerging that the effects of fasting mimicking diet and caloric restriction on the activation of the antitumor immune response could be mediated by the intestinal microbiota remodeling [68]. Several studies have shown that the efficacy of chemotherapy and immunotherapy depend on the abundance and presence of bacterial species in the intestinal microbiota capable of secreting short-chain fatty acids (SCFA: acetic acid, propionic acid, butyric acid) [69][70]. The release of butyric acid inhibits histone deacetylases (HDACs), prevents CD8 exhaustion, and promotes effector CD8 activation by increasing IL12Rb expression through upregulation of the transcriptional regulator ID2 [71]. Calorie restriction exerts the antitumor response against colon and breast cancer by promoting CD8 activation through the enrichment of the microbiota with SCFA producing microbial families (butyric acid and acetic acid) [68].
At the same time, the composition of the microbiota could also influence the activation of the immune system directly through the production of serotonin [72] and indirectly through the release of SCFA, which promotes the transcription of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme of the serotonin biosynthetic pathway, and colon serotonin production by enterochromaffin cells [73]. Serotonin is synthesized from tryptophan and, in addition to its crucial role as a mediator between the gut and the brain, plays an important role in regulating the immune system and tumor progression.
In fact, serotonin mitogenic property favors the progression of cancer [74]. On the other hand, serotonin signaling stimulates T cell activation and proliferation, promotes DC maturation, supports B cell development, enhances NK cell cytotoxicity, and stimulates macrophage polarization towards the M2 phenotype, while inhibiting M1 macrophage polarization [75][76]. However, the conversion of tryptophan to serotonin or kynurenine leads to tryptophan depletion in TME and thus to T-cell exhaustion and immune evasion. Although serotonin plays contradictory roles in regulating the functions of different immune cells, serotonin may have a pro-tumorigenic effect and enhance tumor immune evasion by generating an anti-inflammatory microenvironment.
Furthermore fasting/FMD cycles reverse chemotherapy-induced immunosuppression by promoting hematopoietic stem cell self-renewal (HSC) [77] and enhances cancer immune surveillance by improving memory T cell survival [78]. Indeed, fasting/calorie restriction boosts secondary immune response as it promotes memory T cell migration into the bone marrow where they meet a favorable microenvironment favorable to their survival and protection against chemotherapy [10][77]. Furthermore, T cells subjected to fasting acquire stem features as the lack of nutrients leads to an increase in autophagy and mitochondrial metabolism which causes a reduction in metabolic cofactors, such as acetyl coenzyme A, essential for epigenetic remodeling and cell differentiation. At the same time, the reduction of methionine and its intermediates affects histone methylation and compromises the activation of signaling pathways involved in stemness suppression [79].
Fasting/FMD cycles promote the selective expansion of early/progenitor exhausted effector T cells at the expense of late exhausted effector T cells in breast cancer [42]. Early exhausted effector T cells represent a subpopulation of exhausted/dysfunctional T cells, which correlate with the success of immune checkpoint inhibition and increased patient survival [80][81]. This subpopulation expresses dysfunctional markers such as TOX and PD1, but also exhibit self-renewing capacity and features of memory T cells, associated with the expression of transcriptional regulator T cell factor 1 (TCF1) [82][83][84]. Immune checkpoint blockade reverses immunosuppression and boosts immune response by increasing early exhausted effector T cell proliferation and differentiation in effector T cells, essential for long-term maintenance of persistent T cell responses. mTOR inhibition expands early exhausted effector T cells ex vivo and enhances long term T cell response and the efficacy of immune checkpoint inhibition [85]. Therefore, the frequency of early exhausted T cells is considered to be a predictive biomarker for favorable clinical outcome of checkpoint therapy.
Early exhausted effector T cells display higher mitochondrial mass and better mitochondrial fitness compared with late exhausted effector T cells. These mitochondrial changes are associated with high OXPHOS capacity, essential for supporting the early exhausted effector T cells’ self-renewal [85]. Fasting/FMD promotes the selective expansion of early exhausted effector T cells at the expense of late exhausted effector T cells in the breast cancer model by shifting the metabolism from glycolysis to OXPHOS and increasing b-oxidation of fatty acids [42].
Fasting favors the accumulation and activation of gd T cells in breast tissue and strengthens the anti-tumor immune response of cytotoxic CD8 T cells by producing ketone bodies and inhibiting mTOR activity. γδ T cells, particularly the Vd1+ subtype, can orchestrate an effective anti-tumor response, as supported by the positive correlation of their presence with better prognosis in TNBC patients [86]. Notably, ketone bodies produced by a ketogenic diet have been shown to promote the expansion and activation of gd T cells in the visceral mass [87], while the mTOR inhibition impairs the development of ab T cells but promotes gd T cell generation in the thymus [27][88].
Short-term fasting attenuates monocyte metabolic and inflammatory activity and inhibits monocyte mobilization from the bone marrow through suppression of systemic CCL2 production, leading to a drastic reduction of circulating monocytes that could affect infiltration and the composition of the tumor microenvironment [89]. Furthermore, fasting/FMD cycles reduce the accumulation of immunosuppressive polymorphonuclear (PMN) MDSC in TME, thereby enhancing the response to immunotherapy in breast cancer [42]. Fasting could enhance the efficacy of immune-checkpoint blockade through the production of ketone body, 3-hydroxybutyrate, as demonstrated for ketogenic diet, by preventing the upregulation of PD-L1 on myeloid cells and by expanding CXCR3+ T cells [55].
Fasting/FMD cycles also could enhance the immune response of anticancer therapies by promoting tumor vessel normalization and a reduction in size, number, and density by repressing the secretion of pro-angiogenic factors such as VEGF, factor VIII, inter- leukin-6 [IL-6], TNF-α, and plasminogen activator inhibitor-1 [PAI- 1] in breast cancer [42][50][51][90]. In addition, CR and fasting reduces fibroblast collagen deposition in the TME and cancer fibrosis by inhibiting, respectively, mTOR and TGF-β signaling, which promotes the conversion of fibroblast in cancer associated fibroblast (CAF) [91][92][93][94].
The less dense and viscous stroma, generated by CR and fasting, reduces the secretion of pro-inflammatory and pro-fibrotic cytokines, allows the infiltration of immune cells into the TME, and consequently enhances the diffusion of the anticancer therapy, thus enhancing the efficacy of anticancer treatment in breast cancer model [42][95].

This entry is adapted from the peer-reviewed paper 10.3390/cancers15153898

References

  1. Elia, I.; Schmieder, R.; Christen, S.; Fendt, S.M. Organ-Specific Cancer Metabolism and Its Potential for Therapy. Handb. Exp. Pharmacol. 2016, 233, 321–353.
  2. Mayers, J.R.; Torrence, M.E.; Danai, L.V.; Papagiannakopoulos, T.; Davidson, S.M.; Bauer, M.R.; Lau, A.N.; Ji, B.W.; Dixit, P.D.; Hosios, A.M.; et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 2016, 353, 1161–1165.
  3. Yuneva, M.O.; Fan, T.W.; Allen, T.D.; Higashi, R.M.; Ferraris, D.V.; Tsukamoto, T.; Mates, J.M.; Alonso, F.J.; Wang, C.; Seo, Y.; et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 2012, 15, 157–170.
  4. Pavlova, N.N.; Thompson, C.B. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016, 23, 27–47.
  5. Hofer, S.J.; Davinelli, S.; Bergmann, M.; Scapagnini, G.; Madeo, F. Caloric Restriction Mimetics in Nutrition and Clinical Trials. Front. Nutr. 2021, 8, 717343.
  6. Eriau, E.; Paillet, J.; Kroemer, G.; Pol, J.G. Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy. Cancers 2021, 13, 1260.
  7. Longo, V.D.; Anderson, R.M. Nutrition, longevity and disease: From molecular mechanisms to interventions. Cell 2022, 185, 1455–1470.
  8. Nencioni, A.; Caffa, I.; Cortellino, S.; Longo, V.D. Fasting and cancer: Molecular mechanisms and clinical application. Nat. Rev. Cancer. 2018, 18, 707–719.
  9. de Cabo, R.; Mattson, M.P. Effects of Intermittent Fasting on Health, Aging, and Disease. N. Engl. J. Med. 2019, 381, 2541–2551.
  10. Longo, V.D.; Cortellino, S. Fasting, dietary restriction, and immunosenescence. J. Allergy Clin. Immunol. 2020, 146, 1002–1004.
  11. Taylor, S.R.; Falcone, J.N.; Cantley, L.C.; Goncalves, M.D. Developing dietary interventions as therapy for cancer. Nat. Rev. Cancer. 2022, 22, 452–466.
  12. Lee, C.; Longo, V.D. Fasting vs dietary restriction in cellular protection and cancer treatment: From model organisms to patients. Oncogene 2011, 30, 3305–3316.
  13. Bagherniya, M.; Butler, A.E.; Barreto, G.E.; Sahebkar, A. The effect of fasting or calorie restriction on autophagy induction: A review of the literature. Ageing Res. Rev. 2018, 47, 183–197.
  14. Longo, V.D.; Fontana, L. Calorie restriction and cancer prevention: Metabolic and molecular mechanisms. Trends Pharmacol. Sci. 2010, 31, 89–98.
  15. Cangemi, A.; Fanale, D.; Rinaldi, G.; Bazan, V.; Galvano, A.; Perez, A.; Barraco, N.; Massihnia, D.; Castiglia, M.; Vieni, S.; et al. Dietary restriction: Could it be considered as speed bump on tumor progression road? Tumour Biol. 2016, 37, 7109–7118.
  16. Longo, V.D.; Mattson, M.P. Fasting: Molecular mechanisms and clinical applications. Cell Metab. 2014, 19, 181–192.
  17. De Groot, S.; Pijl, H.; van der Hoeven, J.J.M.; Kroep, J.R. Effects of short-term fasting on cancer treatment. J. Exp. Clin. Cancer Res. 2019, 38, 209.
  18. Raffaghello, L.; Lee, C.; Safdie, F.M.; Wei, M.; Madia, F.; Bianchi, G.; Longo, V.D. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc. Natl. Acad. Sci. USA 2008, 105, 8215–8220.
  19. Lee, C.; Safdie, F.M.; Raffaghello, L.; Wei, M.; Madia, F.; Parrella, E.; Hwang, D.; Cohen, P.; Bianchi, G.; Longo, V.D. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res. 2010, 70, 1564–1572.
  20. Lee, C.; Raffaghello, L.; Brandhorst, S.; Safdie, F.M.; Bianchi, G.; Martin-Montalvo, A.; Pistoia, V.; Wei, M.; Hwang, S.; Merlino, A.; et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. 2012, 4, 124ra127.
  21. Phadngam, S.; Castiglioni, A.; Ferraresi, A.; Morani, F.; Follo, C.; Isidoro, C. PTEN dephosphorylates AKT to prevent the expression of GLUT1 on plasmamembrane and to limit glucose consumption in cancer cells. Oncotarget 2016, 7, 84999–85020.
  22. Lien, E.C.; Westermark, A.M.; Zhang, Y.; Yuan, C.; Li, Z.; Lau, A.N.; Sapp, K.M.; Wolpin, B.M.; Vander Heiden, M.G. Low glycaemic diets alter lipid metabolism to influence tumour growth. Nature 2021, 599, 302–307.
  23. Luo, H.; Chiang, H.H.; Louw, M.; Susanto, A.; Chen, D. Nutrient Sensing and the Oxidative Stress Response. Trends Endocrinol. Metab. 2017, 28, 449–460.
  24. Yoshino, J.; Mills, K.F.; Yoon, M.J.; Imai, S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011, 14, 528–536.
  25. Mai, A.; Cheng, D.; Bedford, M.T.; Valente, S.; Nebbioso, A.; Perrone, A.; Brosch, G.; Sbardella, G.; De Bellis, F.; Miceli, M.; et al. epigenetic multiple ligands: Mixed histone/protein methyltransferase, acetyltransferase, and class III deacetylase (sirtuin) inhibitors. J. Med. Chem. 2008, 51, 2279–2290.
  26. Keppler, B.R.; Archer, T.K. Chromatin-modifying enzymes as therapeutic targets—Part 1. Expert Opin. Ther. Targets 2008, 12, 1301–1312.
  27. Salvadori, G.; Zanardi, F.; Iannelli, F.; Lobefaro, R.; Vernieri, C.; Longo, V.D. Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape. Cell Metab. 2021, 33, 2247–2259.e6.
  28. Caffa, I.; Spagnolo, V.; Vernieri, C.; Valdemarin, F.; Becherini, P.; Wei, M.; Brandhorst, S.; Zucal, C.; Driehuis, E.; Ferrando, L.; et al. Fasting-mimicking diet and hormone therapy induce breast cancer regression. Nature 2020, 583, 620–624.
  29. Fontana, L.; Adelaiye, R.M.; Rastelli, A.L.; Miles, K.M.; Ciamporcero, E.; Longo, V.D.; Nguyen, H.; Vessella, R.; Pili, R. Dietary protein restriction inhibits tumor growth in human xenograft models. Oncotarget 2013, 4, 2451–2461.
  30. Maddocks, O.D.; Labuschagne, C.F.; Adams, P.D.; Vousden, K.H. Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. Mol. Cell 2016, 61, 210–221.
  31. Amelio, I.; Melino, G.; Frezza, C. Exploiting tumour addiction with a serine and glycine-free diet. Cell Death Differ. 2017, 24, 1311–1313.
  32. Mates, J.M.; Sanchez-Jimenez, F.M. Role of reactive oxygen species in apoptosis: Implications for cancer therapy. Int. J. Biochem. Cell Biol. 2000, 32, 157–170.
  33. Di Tano, M.; Raucci, F.; Vernieri, C.; Caffa, I.; Buono, R.; Fanti, M.; Brandhorst, S.; Curigliano, G.; Nencioni, A.; de Braud, F.; et al. Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers. Nat. Commun. 2020, 11, 2332.
  34. Komninou, D.; Leutzinger, Y.; Reddy, B.S.; Richie, J.P., Jr. Methionine restriction inhibits colon carcinogenesis. Nutr. Cancer 2006, 54, 202–208.
  35. Sinha, R.; Cooper, T.K.; Rogers, C.J.; Sinha, I.; Turbitt, W.J.; Calcagnotto, A.; Perrone, C.E.; Richie, J.P., Jr. Dietary methionine restriction inhibits prostatic intraepithelial neoplasia in TRAMP mice. Prostate 2014, 74, 1663–1673.
  36. Gao, X.; Sanderson, S.M.; Dai, Z.; Reid, M.A.; Cooper, D.E.; Lu, M.; Richie, J.P., Jr.; Ciccarella, A.; Calcagnotto, A.; Mikhael, P.G.; et al. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 2019, 572, 397–401.
  37. Yoo, H.C.; Yu, Y.C.; Sung, Y.; Han, J.M. Glutamine reliance in cell metabolism. Exp. Mol. Med. 2020, 52, 1496–1516.
  38. Schvartzman, J.M.; Thompson, C.B.; Finley, L.W.S. Metabolic regulation of chromatin modifications and gene expression. J. Cell Biol. 2018, 217, 2247–2259.
  39. Tischler, J.; Gruhn, W.H.; Reid, J.; Allgeyer, E.; Buettner, F.; Marr, C.; Theis, F.; Simons, B.D.; Wernisch, L.; Surani, M.A. Metabolic regulation of pluripotency and germ cell fate through alpha-ketoglutarate. EMBO J. 2019, 38, e99518.
  40. Qing, G.; Li, B.; Vu, A.; Skuli, N.; Walton, Z.E.; Liu, X.; Mayes, P.A.; Wise, D.R.; Thompson, C.B.; Maris, J.M.; et al. ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 2012, 22, 631–644.
  41. Pan, M.; Reid, M.A.; Lowman, X.H.; Kulkarni, R.P.; Tran, T.Q.; Liu, X.; Yang, Y.; Hernandez-Davies, J.E.; Rosales, K.K.; Li, H.; et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 2016, 18, 1090–1101.
  42. Cortellino, S.; Raveane, A.; Chiodoni, C.; Delfanti, G.; Pisati, F.; Spagnolo, V.; Visco, E.; Fragale, G.; Ferrante, F.; Magni, S.; et al. Fasting renders immunotherapy effective against low-immunogenic breast cancer while reducing side effects. Cell Rep. 2022, 40, 111256.
  43. Lu, Z.; Xie, J.; Wu, G.; Shen, J.; Collins, R.; Chen, W.; Kang, X.; Luo, M.; Zou, Y.; Huang, L.J.; et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat. Med. 2017, 23, 79–90.
  44. Yoshida, K.; Inoue, T.; Nojima, K.; Hirabayashi, Y.; Sado, T. Calorie restriction reduces the incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He mice. Proc. Natl. Acad. Sci. USA 1997, 94, 2615–2619.
  45. Bradey, A.L.; Fitter, S.; Duggan, J.; Wilczek, V.; Williams, C.M.D.; Cheney, E.A.; Noll, J.E.; Tangseefa, P.; Panagopoulos, V.; Zannettino, A.C.W. Calorie restriction has no effect on bone marrow tumour burden in a Vk*MYC transplant model of multiple myeloma. Sci. Rep. 2022, 12, 13128.
  46. Kouidhi, S.; Ben Ayed, F.; Benammar Elgaaied, A. Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy. Front. Immunol. 2018, 9, 353.
  47. Sukumar, M.; Liu, J.; Ji, Y.; Subramanian, M.; Crompton, J.G.; Yu, Z.; Roychoudhuri, R.; Palmer, D.C.; Muranski, P.; Karoly, E.D.; et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Investig. 2013, 123, 4479–4488.
  48. Ma, E.H.; Bantug, G.; Griss, T.; Condotta, S.; Johnson, R.M.; Samborska, B.; Mainolfi, N.; Suri, V.; Guak, H.; Balmer, M.L.; et al. Serine Is an Essential Metabolite for Effector T Cell Expansion. Cell Metab. 2017, 25, 345–357.
  49. Roy, D.G.; Chen, J.; Mamane, V.; Ma, E.H.; Muhire, B.M.; Sheldon, R.D.; Shorstova, T.; Koning, R.; Johnson, R.M.; Esaulova, E.; et al. Methionine Metabolism Shapes T Helper Cell Responses through Regulation of Epigenetic Reprogramming. Cell Metab. 2020, 31, 250–266.e9.
  50. O’Flanagan, C.H.; Smith, L.A.; McDonell, S.B.; Hursting, S.D. When less may be more: Calorie restriction and response to cancer therapy. BMC Med. 2017, 15, 106.
  51. Hursting, S.D.; Dunlap, S.M.; Ford, N.A.; Hursting, M.J.; Lashinger, L.M. Calorie restriction and cancer prevention: A mechanistic perspective. Cancer Metab. 2013, 1, 10.
  52. Pomatto-Watson, L.C.D.; Bodogai, M.; Bosompra, O.; Kato, J.; Wong, S.; Carpenter, M.; Duregon, E.; Chowdhury, D.; Krishna, P.; Ng, S.; et al. Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition. Nat. Commun. 2021, 12, 6201.
  53. Manukian, G.; Kivolowitz, C.; DeAngelis, T.; Shastri, A.A.; Savage, J.E.; Camphausen, K.; Rodeck, U.; Zarif, J.C.; Simone, N.L. Caloric Restriction Impairs Regulatory T cells Within the Tumor Microenvironment After Radiation and Primes Effector T cells. Int. J. Radiat. Oncol. Biol. Phys. 2021, 110, 1341–1349.
  54. Vernieri, C.; Fuca, G.; Ligorio, F.; Huber, V.; Vingiani, A.; Iannelli, F.; Raimondi, A.; Rinchai, D.; Frige, G.; Belfiore, A.; et al. Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer. Cancer Discov. 2022, 12, 90–107.
  55. Ferrere, G.; Tidjani Alou, M.; Liu, P.; Goubet, A.G.; Fidelle, M.; Kepp, O.; Durand, S.; Iebba, V.; Fluckiger, A.; Daillere, R.; et al. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade. JCI Insight 2021, 6, e145207.
  56. Ajona, D.; Ortiz-Espinosa, S.; Lozano, T.; Exposito, F.; Calvo, A.; Valencia, K.; Redrado, M.; Remirez, A.; Lecanda, F.; Alignani, D.; et al. Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade. Nat. Cancer 2020, 1, 75–85.
  57. Di Biase, S.; Lee, C.; Brandhorst, S.; Manes, B.; Buono, R.; Cheng, C.W.; Cacciottolo, M.; Martin-Montalvo, A.; de Cabo, R.; Wei, M.; et al. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. Cancer Cell 2016, 30, 136–146.
  58. Pietrocola, F.; Pol, J.; Vacchelli, E.; Rao, S.; Enot, D.P.; Baracco, E.E.; Levesque, S.; Castoldi, F.; Jacquelot, N.; Yamazaki, T.; et al. Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell 2016, 30, 147–160.
  59. Vella, V.; Lappano, R.; Bonavita, E.; Maggiolini, M.; Clarke, R.B.; Belfiore, A.; De Francesco, E.M. Insulin/IGF Axis and the Receptor for Advanced Glycation End Products: Role in Meta-inflammation and Potential in Cancer Therapy. Endocr. Rev. 2023, 44, 693–723.
  60. Wang, X.; Yang, Q.; Liao, Q.; Li, M.; Zhang, P.; Santos, H.O.; Kord-Varkaneh, H.; Abshirini, M. Effects of intermittent fasting diets on plasma concentrations of inflammatory biomarkers: A systematic review and meta-analysis of randomized controlled trials. Nutrition 2020, 79–80, 110974.
  61. Hung, M.H.; Lee, J.S.; Ma, C.; Diggs, L.P.; Heinrich, S.; Chang, C.W.; Ma, L.; Forgues, M.; Budhu, A.; Chaisaingmongkol, J.; et al. Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma. Nat. Commun. 2021, 12, 1455.
  62. Cortellino, S.Q.V.; Delfanti, G.; Blaževitš, O.; Chiodoni, C.; Maurea, N.; Di Mauro, A.; Tatangelo, F.; Pisati, F.; Shmahala, A.; Lazzeri, S.; et al. Fasting mimicking diet delays cancer growth and reduces immune thearapy- associated cardiovascular and systemic side effects. Nat. Commun. 2023, in press.
  63. Hasegawa, A.; Iwasaka, H.; Hagiwara, S.; Asai, N.; Nishida, T.; Noguchi, T. Alternate day calorie restriction improves systemic inflammation in a mouse model of sepsis induced by cecal ligation and puncture. J. Surg. Res. 2012, 174, 136–141.
  64. Venereau, E.; Casalgrandi, M.; Schiraldi, M.; Antoine, D.J.; Cattaneo, A.; De Marchis, F.; Liu, J.; Antonelli, A.; Preti, A.; Raeli, L.; et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J. Exp. Med. 2012, 209, 1519–1528.
  65. Kazama, H.; Ricci, J.E.; Herndon, J.M.; Hoppe, G.; Green, D.R.; Ferguson, T.A. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 2008, 29, 21–32.
  66. Gdynia, G.; Sauer, S.W.; Kopitz, J.; Fuchs, D.; Duglova, K.; Ruppert, T.; Miller, M.; Pahl, J.; Cerwenka, A.; Enders, M.; et al. The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration. Nat. Commun. 2016, 7, 10764.
  67. Hubert, P.; Roncarati, P.; Demoulin, S.; Pilard, C.; Ancion, M.; Reynders, C.; Lerho, T.; Bruyere, D.; Lebeau, A.; Radermecker, C.; et al. Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy. J. Immunother. Cancer 2021, 9, e001966.
  68. Mao, Y.Q.; Huang, J.T.; Zhang, S.L.; Kong, C.; Li, Z.M.; Jing, H.; Chen, H.L.; Kong, C.Y.; Huang, S.H.; Cai, P.R.; et al. The antitumour effects of caloric restriction are mediated by the gut microbiome. Nat. Metab. 2023, 5, 96–110.
  69. Vetizou, M.; Pitt, J.M.; Daillere, R.; Lepage, P.; Waldschmitt, N.; Flament, C.; Rusakiewicz, S.; Routy, B.; Roberti, M.P.; Duong, C.P.; et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015, 350, 1079–1084.
  70. Routy, B.; Le Chatelier, E.; Derosa, L.; Duong, C.P.M.; Alou, M.T.; Daillere, R.; Fluckiger, A.; Messaoudene, M.; Rauber, C.; Roberti, M.P.; et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018, 359, 91–97.
  71. He, Y.; Fu, L.; Li, Y.; Wang, W.; Gong, M.; Zhang, J.; Dong, X.; Huang, J.; Wang, Q.; Mackay, C.R.; et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8(+) T cell immunity. Cell Metab. 2021, 33, 988–1000.e1007.
  72. Yano, J.M.; Yu, K.; Donaldson, G.P.; Shastri, G.G.; Ann, P.; Ma, L.; Nagler, C.R.; Ismagilov, R.F.; Mazmanian, S.K.; Hsiao, E.Y. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015, 161, 264–276.
  73. Reigstad, C.S.; Salmonson, C.E.; Rainey, J.F., III; Szurszewski, J.H.; Linden, D.R.; Sonnenburg, J.L.; Farrugia, G.; Kashyap, P.C. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. 2015, 29, 1395–1403.
  74. Jiang, S.H.; Hu, L.P.; Wang, X.; Li, J.; Zhang, Z.G. Neurotransmitters: Emerging targets in cancer. Oncogene 2020, 39, 503–515.
  75. Wu, H.; Denna, T.H.; Storkersen, J.N.; Gerriets, V.A. Beyond a neurotransmitter: The role of serotonin in inflammation and immunity. Pharmacol. Res. 2019, 140, 100–114.
  76. Huh, J.R.; Veiga-Fernandes, H. Neuroimmune circuits in inter-organ communication. Nat. Rev. Immunol. 2020, 20, 217–228.
  77. Cheng, C.W.; Adams, G.B.; Perin, L.; Wei, M.; Zhou, X.; Lam, B.S.; Da Sacco, S.; Mirisola, M.; Quinn, D.I.; Dorff, T.B.; et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 2014, 14, 810–823.
  78. Collins, N.; Han, S.J.; Enamorado, M.; Link, V.M.; Huang, B.; Moseman, E.A.; Kishton, R.J.; Shannon, J.P.; Dixit, D.; Schwab, S.R.; et al. The Bone Marrow Protects and Optimizes Immunological Memory during Dietary Restriction. Cell 2019, 178, 1088–1101.e15.
  79. Vodnala, S.K.; Eil, R.; Kishton, R.J.; Sukumar, M.; Yamamoto, T.N.; Ha, N.H.; Lee, P.H.; Shin, M.; Patel, S.J.; Yu, Z.; et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science 2019, 363, eaau0135.
  80. Miller, B.C.; Sen, D.R.; Al Abosy, R.; Bi, K.; Virkud, Y.V.; LaFleur, M.W.; Yates, K.B.; Lako, A.; Felt, K.; Naik, G.S.; et al. Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 2019, 20, 326–336.
  81. Sade-Feldman, M.; Yizhak, K.; Bjorgaard, S.L.; Ray, J.P.; de Boer, C.G.; Jenkins, R.W.; Lieb, D.J.; Chen, J.H.; Frederick, D.T.; Barzily-Rokni, M.; et al. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2018, 175, 998–1013.e20.
  82. Utzschneider, D.T.; Charmoy, M.; Chennupati, V.; Pousse, L.; Ferreira, D.P.; Calderon-Copete, S.; Danilo, M.; Alfei, F.; Hofmann, M.; Wieland, D.; et al. T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections. Immunity 2016, 45, 415–427.
  83. Im, S.J.; Hashimoto, M.; Gerner, M.Y.; Lee, J.; Kissick, H.T.; Burger, M.C.; Shan, Q.; Hale, J.S.; Lee, J.; Nasti, T.H.; et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016, 537, 417–421.
  84. Wu, T.; Ji, Y.; Moseman, E.A.; Xu, H.C.; Manglani, M.; Kirby, M.; Anderson, S.M.; Handon, R.; Kenyon, E.; Elkahloun, A.; et al. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci. Immunol. 2016, 1, eaai8593.
  85. Gabriel, S.S.; Tsui, C.; Chisanga, D.; Weber, F.; Llano-Leon, M.; Gubser, P.M.; Bartholin, L.; Souza-Fonseca-Guimaraes, F.; Huntington, N.D.; Shi, W.; et al. Transforming growth factor-beta-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection. Immunity 2021, 54, 1698–1714.e5.
  86. Silva-Santos, B.; Serre, K.; Norell, H. gammadelta T cells in cancer. Nat. Rev. Immunol. 2015, 15, 683–691.
  87. Goldberg, E.L.; Shchukina, I.; Asher, J.L.; Sidorov, S.; Artyomov, M.N.; Dixit, V.D. Ketogenesis activates metabolically protective gammadelta T cells in visceral adipose tissue. Nat. Metab. 2020, 2, 50–61.
  88. Yang, K.; Blanco, D.B.; Chen, X.; Dash, P.; Neale, G.; Rosencrance, C.; Easton, J.; Chen, W.; Cheng, C.; Dhungana, Y.; et al. Metabolic signaling directs the reciprocal lineage decisions of alphabeta and gammadelta T cells. Sci. Immunol. 2018, 3, eaas9818.
  89. Jordan, S.; Tung, N.; Casanova-Acebes, M.; Chang, C.; Cantoni, C.; Zhang, D.; Wirtz, T.H.; Naik, S.; Rose, S.A.; Brocker, C.N.; et al. Dietary Intake Regulates the Circulating Inflammatory Monocyte Pool. Cell 2019, 178, 1102–1114.e17.
  90. Mukherjee, P.; Abate, L.E.; Seyfried, T.N. Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clin. Cancer Res. 2004, 10, 5622–5629.
  91. Hettiarachchi, S.U.; Li, Y.H.; Roy, J.; Zhang, F.; Puchulu-Campanella, E.; Lindeman, S.D.; Srinivasarao, M.; Tsoyi, K.; Liang, X.; Ayaub, E.A.; et al. Targeted inhibition of PI3 kinase/mTOR specifically in fibrotic lung fibroblasts suppresses pulmonary fibrosis in experimental models. Sci. Transl. Med. 2020, 12, eaay3724.
  92. Lane, H.A.; Wood, J.M.; McSheehy, P.M.; Allegrini, P.R.; Boulay, A.; Brueggen, J.; Littlewood-Evans, A.; Maira, S.M.; Martiny-Baron, G.; Schnell, C.R.; et al. mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin. Cancer Res. 2009, 15, 1612–1622.
  93. Du, W.; Gerald, D.; Perruzzi, C.A.; Rodriguez-Waitkus, P.; Enayati, L.; Krishnan, B.; Edmonds, J.; Hochman, M.L.; Lev, D.C.; Phung, T.L. Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin. Lab. Investig. 2013, 93, 1115–1127.
  94. Lastwika, K.J.; Wilson, W., III; Li, Q.K.; Norris, J.; Xu, H.; Ghazarian, S.R.; Kitagawa, H.; Kawabata, S.; Taube, J.M.; Yao, S.; et al. Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. Cancer Res. 2016, 76, 227–238.
  95. Lv, X.X.; Liu, S.S.; Hu, Z.W. Autophagy-inducing natural compounds: A treasure resource for developing therapeutics against tissue fibrosis. J. Asian Nat. Prod. Res. 2017, 19, 101–108.
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