Table 3.
Metabolomics-based studies related to ICIs or focusing on the development of ICIs.
| Purpose | Related ICIs | Sample | Methods | Comments | Reference | ||
|---|---|---|---|---|---|---|---|
| Subjects (Number) | Matrix | ||||||
| 1 | Target discovery | - | in vitro | T-cells | LC-MS/MS | PD-1 signaling results in metabolic dysregulation, which suggests considerable metabolic interventions of ICIs’ efficacy. | [81] |
| 2 | Target discovery | - | in vitro | T-cells | LC-MS/MS | Mechanistic association between T-cell senescence and aberrant lipid metabolism was introduced as a novel target for cancer immunotherapy. | [82] |
| 3 | Target discovery | - | in vitro and ex vivo (11 patients with nivolumab and TIL therapy) | T-cells and TILs | LC-MS/MS | Sirt2, associated with reprogramming T-cell metabolism, was identified as a new target of cancer immunotherapy. | [83] |
| 4 | Target discovery | - | in vivo and patients with glioblastoma | tissue | LC-MS/MS and GC-MS | IDO1 inhibition mitigated radiation-induced immunosuppression in glioblastoma. | [84] |
| 5 | Target discovery and Biomarker suggestion | Nivolumab, Pembrolizumab |
ICI-treated patients with NSCLC (23) vs. heathy subjects (20) | plasma | LC-MS/MS | IDO1 inhibitors are a promising treatment for NSCLC considering IDO1 activity seemed to a key role in the primary resistance of ICIs. | [85] |
| 6 | Target discovery | Anti-mouse PC-1, Nivolumab | in vitro, patients with glioblastoma (4), and patients with metastatic melanoma (4) | tissue | LC-MS/MS | ICIs induced the IL4I1, which facilitates tumor progression. | [86] |
| 7 | Target discovery | Anti-PD-1 | in vivo and patients with HCC (196) vs. healthy subjects (176) | urine | LC-MS/MS | PRMT5 inhibition demonstrated a synergistic mechanism enhancing anti-tumor immunity and alleviated the resistance to ICIs. | [87] |
| 8 | Target discovery | Anti-mouse PD-1 | in vivo | tissue | LC-MS/MS | nSMase2 overexpression increased anti-PD-1 efficacy in murine melanoma models. | [88] |
| 9 | Target discovery | - | patients with breast cancer (65) | tissue | MALDI-MSI | The accumulation of PI(18:0/20:3) may affect the PD-1-associated immune checkpoint pathway. | [89] |
| 10 | Target discovery | - | in vivo | plasma | LC-MS/MS and GC-MS |
KEAP1/NRF2 pathway alteration induced reprogramming of pentose phosphate pathway connected with tumorigenesis and tumor regression by immune checkpoint inhibition in NSCLC. | [90] |
| 11 | Target discovery | - | in vitro | Breast cancer cells and PDAC cells | 1H-MRS | Chk-α, COX-2, and TGF-β mediated PD-L1 regulation of metabolism. | [91] |
| 12 | Target discovery | - | patients with breast cancer (58) and patients with HCC (29) | data from previous studies | - | UCD is related to an enhanced response to ICI therapy. | [92] |
| 13 | Target discovery and Biomarker suggestion | Anti-mouse PD-1 and Anti-mouse CTLA-4 | in vitro and patients with PDAC | PDAC cells, serum, and tissue | NMR | IL17 inhibitor enhances ICI sensitivity, and tumor lactate was suggested as a promising early biomarker for efficacy of IL17/PD-1 combination. | [93] |
| 14 | Target discovery and Biomarker suggestion | Nivolumab | nivolumab-treated patients with advanced melanoma (78), nivolumab-treated patients with RCC (485), and everolimus-treated patients with RCC (349) | serum | LC-MS/MS | The combination of a PD-1 inhibitor with IDO/TDO inhibitors was suggested in that worse overall survival associated with simultaneous elevation of resistance and serum kynurenine/tryptophan ratio. | [94] |
| 15 | Biomarker suggestion | Nivolumab and Pembrolizumab | ICI-treated patients with urological cancer (28) | serum | LC-MS/MS | VLCFA-containing lipids are potential predictive biomarkers for ICIs’ response. | [95] |
| 16 | Efficacy evaluation | Nivolumab and Pembrolizumab | ICI-treated patients with NSCLC (19) | plasma | LC-MS/MS | Tryptophan metabolites may become potential predictive biomarkers for the efficacy of the ICIs. | [96] |
| 17 | Biomarker suggestion and Efficacy evaluation | Nivolumab and Pembrolizumab | ICI-treated patients with NSCLC (50) | serum | NMR | The metabolomic fingerprint of serum is a potential biomarker for the response of ICIs. | [97] |
| 18 | Method development | - | patients with melanoma (-) | stool | LC-MS/MS | A comprehensive approach to fecal sample collection and metabolites profiling of gut microbiome were demonstrated. | [98] |
| 19 | Biomarker suggestion | Nivolumab | nivolumab-treated patients with NSCLC (7), NSCLC patients without nivolumabtreatment (4) vs. healthy subjects (8) | stool | GC-MS/SPME and NMR | Microbiota-Linked Biomarkers, including SCFAs, were introduced through network analysis. | [99] |
| 20 | Efficacy evaluation | Nivolumab | nivolumab-treated patients with NSCLC (11) | stool | GC-MS/SPME and 1H-NMR | The identification of microbiota-linked “indicators” is a potential strategy for the prediction of responders, in that gut microbiota metabolic pathways affect the response of ICIs. | [100] |
| 21 | Biomarker suggestion | Nivolumab | nivolumab-treated patients with NSCLC (22) | serum and stool | GC-MS/SPME and NMR | An integrated parameter was proposed to identify good responders for nivolumab treatment. | [101] |
| 22 | Efficacy evaluation | Anti-mouse PD-1, Atezolizumab, Nivolumab, and Pembrolizumab | in vivo and ICI-treated patients with NSCLC (96) vs. healthy subjects (139) | serum and stool | LC-MS/MS | Bifidobacterium bifidum strains make a synergistic effect with ICIs to reduce tumor burden. | [102] |
| 23 | Efficacy evaluation | Nivolumab, and Pembrolizumab | ICI-treated patients of multiple cancers (52) | plasma and stool | LC-MS/MS | Fecal SCFA concentration may affect PD-1 inhibitors’ efficacy. | [103] |
| 24 | Efficacy evaluation | Nivolumab, Pembrolizumab, and Sintilimab | nivolumab-treated patients with NSCLC (4), pembrolizumab-treated patients with NSCLC (42), and sintilimab-treated patients with NSCLC (17) | stool | - | The correlation between intestinal microbiome β-diversity and the response of anti-PD-1 in NSCLC was indicated. | [104] |
Chk-α, choline kinase-α; COX-2, prostaglandin-endoperoxide synthase 2; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; IDO, indoleamine-2,3-dioxygenase 1; IL4I1, interleukin-4-induced-1; KEAP1, Kelch-like ECH-associated protein 1; KMO, kynurenine monooxygenase; KYNU, kynureninase; LC, liquid chromatography; MALDI, Matrix-Assisted Laser Desorption Ionization; MRS, magnetic resonance spectroscopy; MS/MS, tandem mass spectrometry; MSI, mass spectrometry imaging; NMR, nuclear magnetic resonance; NRF2, nuclear factor erythroid-2-related factor 2; NSCLC, non-small cell lung cancer; PBMC, peripheral blood mononuclear cells; PDAC, pancreatic ductal adenocarcinoma; PRMT5, Protein arginine N-methyltransferase 5; RCC, renal cell carcinoma; SCFA, short-chain fatty acid; Sirt2, NAD+-dependent deacetylase; TDO, tryptophan 2,3-dioxygenase; TGF-β, Transforming growth factor β; TIL, tumor-infiltrating lymphocytes; TN, triple-negative; UCD, urea cycle dysregulation; UV/Vis, UV-Vis spectrophotometer.