Can tumor cells take it all away?

Tumor cells utilize glucose to engage in aerobic glycolysis, fulfilling their metabolic demands for extensive proliferation. A recent study Nature discovers that tumor-infiltrating myeloid exhibit a superior uptake capacity over tumor cells, which present enhanced glutamine metabolism, suggesting nutrient partitioning the TME might be more complex than previously thought. take up enormous amounts of and undergo glycolysis even under conditions (known as or Warburg effect) (Vander Heiden et al., 2009Vander M.G. Cantley L.C. Thompson C.B. Understanding effect: requirements cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (9348) Google Scholar). Although inefficient ATP production, generates building blocks support proliferation cells. As consequence elevated consumption by level interstitial fluid decreases while lactate accumulates (Sullivan 2019Sullivan M.R. Danai L.V. Lewis C.A. Chan S.H. Gui D.Y. Kunchok T. Dennstedt E.A. Vander Muir A. Quantification microenvironmental metabolites murine cancers reveals determinants availability.eLife. 2019; 8: e44235Crossref (161) Moreover, increased glycolytic activity is negatively correlated with T infiltration human cancers, inhibiting significantly enhances anti-tumor response preclinical models (Cascone 2018Cascone McKenzie J.A. Mbofung R.M. Punt S. Wang Z. Xu C. Williams L.J. Bristow Carugo al.Increased characterizes immune resistance adoptive therapy.Cell Metab. 2018; 27: 977-987.e4Abstract Full Text PDF (238) These features currently prevailing notion microenvironment ( ) can metabolically restricted milieu infiltrating thereby promoting evasion inducing dysfunction (Ho 2015Ho P.C. Bihuniak J.D. Macintyre A.N. Staron M. Liu X. Amezquita R. Tsui Y.C. Cui G. Micevic Perales J.C. al.Phosphoenolpyruvate checkpoint responses.Cell. 2015; 162: 1217-1228Abstract (731) In work, Reinfeld 2021Reinfeld B.I. Madden M.Z. Wolf M.M. Chytil Bader J.E. Patterson A.R. Sugiura Cohen A.S. Ali Do B.T. al.Cell-programmed tumour microenvironment.Nature. 2021; (Published online April 7, 2021)https://doi.org/10.1038/s41586-021-03442-1Crossref (116) Scholar made use positron emission tomography (PET) tracer 18F-fluorodeoxyglucose (FDG) measure MC38 CT26 mouse models. The authors reveal not only but also particular (TIMs), are able significant within TME. Interestingly, TIMs highest among TME-resident other types (Figure 1), presumably due mTOR activation expression transporter 1 (GLUT1) hexokinase. Overall, seem particularly active they display mitochondrial activities Targeting mTORC1 inhibition suppresses TIMs, sensitive compared Despite lower per cell, this were found consume 60% available glucose, predominant presence TME, higher accounted 30% tumor. Similarly, have been possess responsible majority Thus, indeed dominant consumers closely followed TIMs. propose idea selectively nutrients based on cell-intrinsic programs rather being determined limitation Notably, transport resulted an increase all populations restriction, promising approach treat cancer (Leone 2019Leone R.D. Zhao L. Englert J.M. Sun I.M. Oh M.H. I.H. Arwood M.L. Bettencourt I.A. Patel C.H. Wen J. al.Glutamine blockade induces divergent overcome evasion.Science. 366: 1013-1021Crossref (283) Scholar), act partially through boosting Intriguingly, al. reported levels similar between healthy kidney tissue renal carcinomas patients. This finding suggests deprivation abundance general types. Furthermore, highlights importance concept targeting unexpectedly disturb crosstalk different thus impacting fitness usage was documented decades ago (Frauwirth Thompson, 2004Frauwirth K.A. Regulation lymphocyte metabolism.J. Immunol. 2004; 172: 4661-4665Crossref (275) availability regulate effector function (Cham Gajewski, 2005Cham C.M. Gajewski T.F. Glucose regulates IFN-gamma production p70S6 kinase CD8+ cells.J. 2005; 174: 4670-4677Crossref (215) With effect, has subject many studies. study, showed lymphocytes (TILs) obtain comparable amount splenic do models, raises possibility competition may exist (Chang 2015Chang Qiu O’Sullivan D. Buck M.D. Noguchi Curtis Chen Q. Gindin Gubin van der Windt G.J. al.Metabolic driver progression.Cell. 1229-1241Abstract (1421) PET tracers, such FDG, indicate cell’s taking glucose; however, since FDG given saturated amounts, does reflect typically although TILs at lymphocytes, it remains unknown whether acquire sufficient actions . Considering spatial distribution altered vasculature tumors, detailed analyses unveil nature stromal would provide critical foundation deciphering immunosuppressive Taken together, raise solely consumed evenly partitioned populations. further underpins differential nutrients, subsets play role tailoring responses differentiation status thought, considerations will understand interactions tumors. heterogeneity tumors patients, future studies need decipher how cellular compositions modulate dependencies therapeutic outcomes targeting. help tailor targeted therapies modulating immunometabolism declare no competing interests.