Enhancing CD8 T Cell Fatty Acid Catabolism Within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2017 Sep 13

PMID 28898698

Citations 307

Authors

Ying Zhang

Raj Kurupati

Ling Liu

Xiang Yang Zhou

Gao Zhang

Abeer Hudaihed

Flavia Filisio

Wynetta Giles-Davis

Xiaowei Xu

Giorgos C Karakousis

Lynn M Schuchter

Wei Xu

Ravi Amaravadi

Min Xiao

Norah Sadek

Clemens Krepler

Meenhard Herlyn

Gordon J Freeman

Joshua D Rabinowitz

Hildegund C J Ertl

Affiliations

Soon will be listed here.

Abstract

How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain poorly understood. Using mouse melanoma models, we report that CD8 TILs enhance peroxisome proliferator-activated receptor (PPAR)-α signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8 TILs' effector functions, although co-inhibitor expression increases during tumor progression regardless of CD8 TILs' antigen specificity. Further promoting FA catabolism improves the CD8 TILs' ability to slow tumor progression. PD-1 blockade delays tumor growth without changing TIL metabolism or functions. It synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and even complete cures.

Citing Articles

Fatty acid metabolism shapes immune responses in chronic lymphocytic leukemia.

Zhang Y, Ma J, Li P, Lu K, Han Y, Hu X Biomark Res. 2025; 13(1):42.

PMID: 40075418 PMC: 11905569. DOI: 10.1186/s40364-025-00753-7.

CRSP8-driven fatty acid metabolism reprogramming enhances hepatocellular carcinoma progression by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

Lin Y, Liang Z, Weng Z, Liu X, Zhang F, Chong Y J Exp Clin Cancer Res. 2025; 44(1):93.

PMID: 40069732 PMC: 11895297. DOI: 10.1186/s13046-025-03329-3.

A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8 T cell fitness in solid tumours.

Pretto S, Yu Q, Bourdely P, Trusso Cafarello S, Van Acker H, Verelst J Nat Metab. 2025; .

PMID: 40065102 DOI: 10.1038/s42255-025-01233-w.

The CD64/CD28/CD3ζ chimeric receptor reprograms T-cell metabolism and promotes T-cell persistence and immune functions while triggering antibody-independent and antibody-dependent cytotoxicity.

Caratelli S, De Paolis F, Silvestris D, Baldari S, Salvatori I, Tullo A Exp Hematol Oncol. 2025; 14(1):17.

PMID: 39962623 PMC: 11834217. DOI: 10.1186/s40164-025-00601-2.

Sorafenib enhanced the function of myeloid-derived suppressor cells in hepatocellular carcinoma by facilitating PPARα-mediated fatty acid oxidation.

Li C, Xiong L, Yang Y, Jiang P, Wang J, Li M Mol Cancer. 2025; 24(1):34.

PMID: 39876004 PMC: 11773820. DOI: 10.1186/s12943-025-02238-5.

References

Finlay D, Rosenzweig E, Sinclair L, Feijoo-Carnero C, Hukelmann J, Rolf J . PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med. 2012; 209(13):2441-53. PMC: 3526360. DOI: 10.1084/jem.20112607. View

Balmer M, Ma E, Bantug G, Grahlert J, Pfister S, Glatter T . Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function. Immunity. 2016; 44(6):1312-24. DOI: 10.1016/j.immuni.2016.03.016. View

Crompton J, Sukumar M, Roychoudhuri R, Clever D, Gros A, Eil R . Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 2014; 75(2):296-305. PMC: 4384335. DOI: 10.1158/0008-5472.CAN-14-2277. View

Hamanaka R, Chandel N . Targeting glucose metabolism for cancer therapy. J Exp Med. 2012; 209(2):211-5. PMC: 3280882. DOI: 10.1084/jem.20120162. View

Zou W, Wolchok J, Chen L . PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016; 8(328):328rv4. PMC: 4859220. DOI: 10.1126/scitranslmed.aad7118. View

Ohta A, Diwanji R, Kini R, Subramanian M, Ohta A, Sitkovsky M . In vivo T cell activation in lymphoid tissues is inhibited in the oxygen-poor microenvironment. Front Immunol. 2012; 2:27. PMC: 3342240. DOI: 10.3389/fimmu.2011.00027. View

McNamee E, Korns Johnson D, Homann D, Clambey E . Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol Res. 2012; 55(1-3):58-70. PMC: 3919451. DOI: 10.1007/s12026-012-8349-8. View

Bucks C, Norton J, Boesteanu A, Mueller Y, Katsikis P . Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion. J Immunol. 2009; 182(11):6697-708. PMC: 2923544. DOI: 10.4049/jimmunol.0800997. View

Martinez-Outschoorn U, Lin Z, Whitaker-Menezes D, Howell A, Sotgia F, Lisanti M . Ketone body utilization drives tumor growth and metastasis. Cell Cycle. 2012; 11(21):3964-71. PMC: 3507492. DOI: 10.4161/cc.22137. View

10.

Parry R, Chemnitz J, Frauwirth K, Lanfranco A, Braunstein I, Kobayashi S . CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005; 25(21):9543-53. PMC: 1265804. DOI: 10.1128/MCB.25.21.9543-9553.2005. View

11.

Siska P, Beckermann K, Mason F, Andrejeva G, Greenplate A, Sendor A . Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight. 2017; 2(12). PMC: 5470888. DOI: 10.1172/jci.insight.93411. View

12.

Mueller S, Ahmed R . High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A. 2009; 106(21):8623-8. PMC: 2688997. DOI: 10.1073/pnas.0809818106. View

13.

Tatsis N, Fitzgerald J, Reyes-Sandoval A, Harris-McCoy K, Hensley S, Zhou D . Adenoviral vectors persist in vivo and maintain activated CD8+ T cells: implications for their use as vaccines. Blood. 2007; 110(6):1916-23. PMC: 1976365. DOI: 10.1182/blood-2007-02-062117. View

14.

OSullivan D, van der Windt G, Huang S, Curtis J, Chang C, Buck M . Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity. 2014; 41(1):75-88. PMC: 4120664. DOI: 10.1016/j.immuni.2014.06.005. View

15.

Zhang Y, Ertl H . The effect of adjuvanting cancer vaccines with herpes simplex virus glycoprotein D on melanoma-driven CD8+ T cell exhaustion. J Immunol. 2014; 193(4):1836-46. PMC: 4254702. DOI: 10.4049/jimmunol.1302029. View

16.

Takahashi S, Iizumi T, Mashima K, Abe T, Suzuki N . Roles and regulation of ketogenesis in cultured astroglia and neurons under hypoxia and hypoglycemia. ASN Neuro. 2014; 6(5). PMC: 4187005. DOI: 10.1177/1759091414550997. View

17.

Dalgleish A . Therapeutic cancer vaccines: why so few randomised phase III studies reflect the initial optimism of phase II studies. Vaccine. 2011; 29(47):8501-5. DOI: 10.1016/j.vaccine.2011.09.012. View

18.

Kaech S, Cui W . Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012; 12(11):749-61. PMC: 4137483. DOI: 10.1038/nri3307. View

19.

Ho P, Bihuniak J, Macintyre A, Staron M, Liu X, Amezquita R . Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015; 162(6):1217-28. PMC: 4567953. DOI: 10.1016/j.cell.2015.08.012. View

20.

Hamid O, Robert C, Daud A, Hodi F, Hwu W, Kefford R . Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013; 369(2):134-44. PMC: 4126516. DOI: 10.1056/NEJMoa1305133. View