Table 1.

Comparison between T and NK cell recognition mechanisms, metabolic features, approaches to improve effectivity of adoptive cell transfer, CAR designs boosting their metabolism and strategies to improve metabolic fitness of CAR-expressing cells.

Features	Active Effector T Cell	Active Effector NK Cell
Immune cell activation mechanisms	TCR engagement via recognition of peptides onto MHC-I in target cells [7]	No requirement of MHC-I on target cells, activation through stimulatory receptors [172]
Energetic metabolism	aerobic glycolysis and OXPHOS via the TCA cycle [7,20].	aerobic glycolysis and OXPHOS via the CMS [215]
Metabolic phenotype	glycolytic [7]	glycolytic [215]
Energetic sources	glucose and glutamine [20]	glucose [215]
Metabolic regulators	PI3K/Akt/mTORC1 pathway cMyc, HIF-1α, glutamine [7]	mTORC1 dependent on and independent of PI3K/Akt pathway cMyc, SREBP, glutamine [215]
Metabolism of memory (-like) phenotype	OXPHOS [34]	OXPHOS [215]
Metabolic approaches to enhance immune cell metabolism, effector functions and persistence upon adoptive cell transfer	In vivo inhibition of the lactate transporters MCT1 and MCT4 by diclofenac in a melanoma mouse model renders tumors sensible to PD1 blockade [102]	Pharmacological inhibition of SREBPs in a melanoma mouse model controls tumor burden [222]
	Glucose restriction for expansion of CD8 T+ cells prior to adoptive transfer into a lymphoma mouse model drives better tumor burden control [92]	Ex vivo pharmacological inhibition of fructose-1,6-biphosphatase in infiltrating NK cells from lung tumors in mice enhances glycolysis in vitro and in vivo tumor control upon adoptive cell transfer [229]
	In vitro and ex vivo administration of acetate in glucose-restricted CD8+ T cells and exhausted T cells, respectively, increases cytokine expression. Silencing of the acetyl-CoA synthetase controls better the tumor burden of a lymphoma mouse model [33]
	Overexpression of PEP carboxykinase 1 [49] and PGC1α [42] in T cells transferred into melanoma-bearing mice lead to higher tumor cytotoxicity.	Pharmacological inhibition of GSK3 in NK cells from PB expanded with IL15 increases maturation and tumor cytotoxicity in mouse model of ovarian cancer [276]
	Oral bicarbonate in tumor-bearing mice controls tumor growth upon PD1 and/or CTL4 blockade and upon adoptive T cell transfer in melanoma-bearing mice [234]
Advantages of adoptive CAR-expressing cell transfer as a therapy	Commercial approval of several CAR T cell therapies by the FDA [277] T cells are more suitable for bioengineering by classical viral vector transduction [257]	No need for cells of autologous origin [172] Less prone to GVHD [172]
CAR designs and metabolic fitness	4-1BB-containing CAR: OXPHOS metabolism [75] and longer in vivo persistence [72] CD28-containing CAR: glycolytic metabolism [75] and shorter in vivo persistence [72]	NKG2D-expressing CAR resistant to the immune and metabolic suppressor TGFβ drives MDSCs clearance and better tumor burden control of CAR T cells targeting neuroblastoma in mice [261].
	Hypoxia-inducible CAR expression for better tumor control in mouse models of ovarian cancer and neck and head cancer [120]	IL15-expressing CAR increases in vivo persistence and survival of a lymphoma mouse model [278]
Metabolic strategies to improve fitness of CAR-expressing cells in the TME	IL15 stimulation of CAR T cells reduces glycolysis, increases OXPHOS and FAO genes and leads to a stem cell memory phenotype, high proliferation, longer in vivo persistence, tumor burden control and survival of a lymphoma model [78]	Cytokine-induced memory-like (ML) NK cells modified with a CAR displayed better tumor burden control in lymphoma mouse models as compared to conventional CAR NK cells and ML NK cells [236]
	LDH depletion in prostate tumors improved cancer growth control by CAR T cells [98]	Genetic deletion of the IL15 immune checkpoint in IL15-expressing CAR NK cells increases mTOR and cMyc pathways, glycolytic rates and survival of a lymphoma model [264]
	A2AR deficiency in mouse and human CAR T cells improved tumor burden control in breast and ovarian cancer mouse models, respectively [123]	NK cell expansion with IL21-expressing feeder cells increases the expression of several metabolic genes, glucose uptake and promotes a less differentiated phenotype while enhancing tumor cytotoxicity in lymphoma mouse models [262]
	PD1 silencing and expression of IL12 in PD1 deficient CAR T cells increased survival of a lymphoma xenograft mouse model [142]