Table 1.

Metabolic signaling regulators that improve CAR-T cell destiny and reverse exhaustion

Target	Compounds	FDA approval	Model	Outcome	References
PI3K	LY294002 IC87114	No	1. MOLM-13-CD19 cell line 2. NSG mice AML model	Increasing TN and TCM populations of CD33 CAR-T in vivo Improving CAR-T cell persistence and reducing tumor burden in vivo	[119]
PDK Glycolysis	Dichloroacetate	Yes	1. Hepatocellular carcinoma (HCC) cell lines 2. HCC-bearing mice model	Increasing TN and TCM percentages Reducing lactate-mediated immunosuppression	[168]
mTOR	Rapamycin	Yes	Acute lymphocytic choriomeningitis virus infection mice model	Enhancing the formation of memory CD8 T cells during the naïve to effector T cell differentiation phase and the effector to memory transition phase in vivo Improving the functional qualities of the memory CD8 T cells in vivo	[117]
Akt	A-443654	No	LCMV-infected mice model	Rescuing short-lived effector cells from deletion due to sustained Akt activation Enhancing P14 CD8 TEM cells in vivo	[118]
Akt	Akti-1/2	No	1. CD19 + lymphoid leukemic cell line 2. CD19 + tumor-bearing immunodeficient mice model	Preventing CAR-T cell differentiation Increasing cytokine production and cytotoxicity Exhibiting greater anti-tumor efficacy and expansion in vivo	[124]
BATF c-Myc	JQ1	No	1. K562 cell line, CD19 + leukemia cell line NALM-6,melanoma cell line A375 2. ALL or melanoma-bearing NSG mice model	Promoting the maintenance of TSCM and TCM phenotypes, persistence and antitumor effects of CAR-T cells in vivo	[169]
PI3Kγ PI3Kδ	IPI-549 CAL-101 TGR-1202	No	1. B16F10 (H-2b) melanoma cell line 2. K562-mesothelinexpressing cell line 3. pmel-1 TCR-transgenic mice model	Sole blockade of PI3Kγ or PI3Kδ, but not dual inhibition, induces a naive/stem memory-like profile and enhances in vivo antitumor immunity of infused CD8+ T cells PI3Kδ inhibition improves cytotoxicity of Meso-CAR T cells	[121]
PI3Kδ	Idelalisib	Yes	1. PBMCs fromconsenting DLBCL patients and healthy controls 2. NSG mice model 3. B6 SJL mice lymphoma model	Enhancing the expansion and functionality of CAR-T cells in vitro Enhancing DLBCL patient T cells persistence in vivo Enhancing anti-tumor activity of OT-T cells in a murine lymphoma model	[120]
PGC-1α PPAR-α	Bezafibrate Fenofibrate	Yes	1. Melanoma mice model 2. Skin sarcoma BALB/c mice model	Promoting FAO Improving CD8+ TIL functions Synergizing with PD-1 blockade	[133, 136, 170]