Table 4.
The main preclinical studies of metabolism-based therapy.
| Process | Effects | Tumor type | Species | Combined therapy | Ref |
|---|---|---|---|---|---|
| Glycolysis |
Pyruvate
1. Ex vivo (co-cultured exogenous pyruvate and CD8+ TILs); 2. Enhanced both glycolysis and OXPHOS; 3. Improved cytokine production (IFN-γ, TNF-α); |
Melanoma (B16) |
M | / | (71) |
| Pyruvate metabolism |
IL-10 Fc
1. In vivo; 2. Limited tumor growth; 3. Expanded terminally exhausted subsets (self-renewal); 4. Improved cytotoxicity of terminally exhausted subsets; |
Melanoma (B16); Colon cancer (CT26) |
M | PD1/PDL1 blockade | (72) |
| Lipid peroxidation |
GPX4 OE (CAR-T cells overexpressing GPX4)
1. ACT (transfer of GPX4 OE into tumor models); 2. Enhanced tumor control; 3. Increased the number of CD8+ TILs; 4. GPX4 OE showed enhanced cytokine production (TNF, IFN-γ); |
Melanoma (B16); Colon cancer (MC38) |
M | / | (36) |
| ER stress |
ER-stress inhibitor STF or simvastatin
1. ACT (transfer of CD8+ T cells pre-treatment with drugs); 2. Enhanced tumor control; 3. Decreased the expression of PD1 and 2B4; |
Melanoma (B16); Colon cancer (MC38) |
M | / | (37) |
| Mitochondrial metabolism |
Nicotinamide ribose
1. Oral treatment; 2. Better control of tumor; 3. Increased cytokine production (IFN, TNF); |
Melanoma (YUMM1.7) |
M | PD1/PDL1 blockade | (39) |
|
N- acetylcysteine (NAC)
1. ACT (transfer of T cells pre-treatment with NAC); 2. Suppressed tumor growth; 3. Increased effector function (Granzyme B, TNF, IFN); |
Melanoma (B16) |
M | PD1/PDL1 blockade | (38) | |
|
Knockdown pac1
1. Evaluated the anti-tumor effects of knockdown of pac1; 2. Limited tumor growth; 3. Increased CD8+ TILs; 4. Increased production of IFN-γ and TNF in CD8+ TILs; 5. Potentiated CD8+ T cell response; |
Colon cancer (AOM-DSS model); Melanoma (B16-F10) |
M | / | (40) | |
|
PGC1αOE (CAR-T cells overexpressing PGC1α)
1. ACT (transfer of CAR-T cells overexpressing PGC1α into tumor model); 2. Limited tumor growth; 3. PGC1αOE without progenitor exhausted signature; 4. Altered differentiation and avoided the differentiation of TEXs; |
Melanoma (B16); |
M | / | (20) | |
| Hypoxia |
Metformin
1. In vivo 2. Monotherapy is not effective; 3. Increased the effects of PD1/PDL1 blockade; |
Melanoma (B16); Colon cancer (MC38) |
M | PD1/PDL1 blockade | (74) |
|
Axitinib (tyrosine kinase inhibitor)
1. In vivo; 2. Decreased tumor burden and improved survival; 3. Decreased expression of PD1 and TIM3; 4. Increased production of IFN and TNF; |
Melanoma (B16); |
M | PD1/PDL1 blockade | (20) |
The table summarized the main preclinical studies of metabolism-based therapy. Tumor: tumor cell lines in mouse model or method. M, mouse; Ref, references; ACT, adoptive cell transfer therapy.