Table 1.
Current research progress of CD8+ T cell metabolic targeting combined with ICIs therapy.
| Metabolic agent | Immune-checkpoint inhibitor combination partner | Cancer types | Status | Effects | Reference |
|---|---|---|---|---|---|
| Targeting lipid metabolism | |||||
| CD36 gene knockout | InVivoPlus anti-mouse PD-1 (clone RMP 1-14) | Melanoma | Animal experiments | Extends mouse survival | (17) |
| Avasimibe (ACAT inhibitor) |
Nivolumab | HBV-related HCC | Cell experiment | Enhances responsiveness to PD-1 blockade | (41) |
| Fenofibrate (PPAR-α agonist) |
α-PD-1 Ab (clone 29F.1A12) |
Melanoma | Animal experiments | Improves CD8+ TIL functions and works in synergy with PD-1 blockade to delay tumor growth | (73) |
| Bezafibrate (PGC-1α/PPAR agonist) |
Anti–PD-L1 (clone 1-111A.4) |
Colon carcinoma | Animal experiments | Combination therapy enhances survival and proliferation of tumor-reactive CTLs. | (75) |
| Targeting glucose metabolism | |||||
| AR-C155858 (MCT1 inhibitor) |
Nivolumab | Colon carcinoma | Animal experiments | Decreases the frequency of Treg cells and PD-1 expression by Treg cells and increases activated CD8+ T cells in the intrahepatic TME | (46) |
| LDH-A knockdown | Anti-PD-1 mAb (Bioxcell, Lebanon, NH, USA) |
pMMR colorectal cancer | Animal experiments | LDH-A inhibition can improve the efficacy of PD-1 blockade in a pMMR CRC xenograft model. | (87) |
| Targeting amino acid metabolism | |||||
| CB-839 (Glutaminase inhibitor) |
InVivoPlus anti-mouse PD-1 (clone RMP 1-14) |
KRAS-mutant lung adenocarcinoma | Animal experiments | Inhibits clonal expansion and activation of CD8+ T cells | (113) |
| V9302 (Glutamine metabolism inhibitor) |
InVivoPlus anti-mouse PD-1 (clone RMP 1-14) |
Breast cancer | Animal experiments | Strengthens CD8+ T cell infiltration and activation, and sensitizes breast cancer to PD-1 blockade therapy | (114) |
| Epacadostat (IDO1 inhibitor) | Pembrolizumab | Melanoma | Completed/ Phase 3 |
Does not improve progression-free survival or overall survival | NCT02752074 |
| Ipilimumab | Melanoma | Terminated/ Phase 1/2 |
Demonstrates clinical and pharmacologic activity and is well-tolerated in patients with advanced melanoma | NCT01604889 | |
| Pembrolizumab | Neck Squamous Cell Carcinoma | Active/ Phase 2 |
Unknown | NCT03823131 | |
| NCT03832673, NCT04463771, NCT03589651, NCT04586244 | |||||
| Targeting amino acid metabolism | |||||
| BMS-986205 (IDO1 inhibitor) |
Nivolumab | Muscle-invasive bladder cancer | Recruiting/ Phase 3 |
Unknown | NCT03661320 |
| Nivolumab | Endometrial Adenocarcinoma | Active/ Phase 2 |
Unknown | NCT04106414 | |
| NCT03519256, NCT03854032, NCT03695250, NCT03792750, NCT03459222 … | |||||
| L-arginine supplementation | Anti-mouse PD-1 (clone RMP 1-14) |
Colon carcinoma | Animal experiments | Increases the proportions of tumor peptide-specific CD8+ T cells in draining lymph nodes and increases the number of cured mice that are treated with CP and anti-PD-1 antibody | (124) |
| Methionine supplementation | Anti-mouse PD-L1 (Clone: 10F.9G2) |
Ovarian cancer Melanoma |
Animal experiments | Increases T cell tumor infiltration and mediates synergistic antitumor effects | (101) |
| Targeting adenosine metabolism | |||||
| Anti-mouse CD73 mAb (clone TY/23) |
Anti-mouse PD-1 mAb (clone RMP1-14) Anti-mouse CTLA-4 mAb (clone 9H10 and UC10-4F10) |
Colon carcinoma Prostate cancer Breast carcinoma |
Animal experiments | CD73 blockade enhances anti-PD-1/CTLA-4 mAb therapy via IFN-γ and CD8+ T cells | (129) |
| MEDI9447 (CD73 ectonucleotidase activity inhibitor) |
Anti-PD1 antibody (AMP-514) |
Colon carcinoma Breast carcinoma |
Animal experiments | Increases the number of CD8+ effector cells and activated macrophages | (130) |
| BMS-986179 (Anti-CD73 antibody) |
Nivolumab | Malignant Solid Tumor | Completed/Phase 1/2 | A total of 59 patients received bms-986179 monotherapy or combination therapy with nivolumab, of which 7 patients achieved partial response and 10 patients achieved stable disease. The safety of combination therapy was consistent with nivolumab monotherapy. | NCT02754141 |
|
SCH58261, SYN115 (A2AR antagonist) |
Anti-mouse PD-1 mAb (clone RMP1-14) |
Breast carcinoma | Animal experiments | Combination of PD-1 and A2A blockade significantly enhances the IFNγ production of tumor-infiltrating CD8+ T lymphocytes | (132) |
| Ciforadenant (A2aR inhibitor) |
Atezolizumab | Renal Cell Cancer | Completed/Phase 1 | Increases recruitment of CD8+ T cells into the tumor and broadens the circulating T-cell repertoire. | NCT02655822 |
| Etrumadenant (Dual adenosine receptor antagonist) |
Zimberelimab | Renal Cell Cancer | Recruiting/ Phase 2 |
Unknown | NCT05024097 |
| Rhein (CD38 inhibitor) |
Anti-PD-L1 (clone 9G2) |
Lung cancer | Animal experiments | Increases activated CD8+ T cells and memory CD8+ T cells and substantially reduces primary tumor burden and metastases | (138) |