Table 1.
Molecular mechanisms of immune checkpoints regulating tumor proliferation.
| Immune Checkpoint | Tumor | Molecular Mechanisms | PMID |
|---|---|---|---|
| PD1/PD-L1 | Head and neck squamous cell carcinoma | ①The downregulation of CMTM6 inhibits the expression of PD-L1 ②The decrease in PD-L1 further inhibits SCC7 cell proliferation by Wnt/β-catenin signaling pathway ③The decrease in PD-L1 induces the infiltration of CD4+ and CD8+ T cells |
24871033 |
| Uveal melanoma | ①PD1 promotes the expression of CyclinD1 and mTOR signaling pathway ②PD1 inhibits the expression of DR4 |
32686562 | |
| Thyroid cancer | ①PD1 promotes the accumulation SH2 phosphatas ②The accumulation SH2 phosphatase dephosphorylates tyrosine 32 and activates Ras, triggering the cascade of MAPK |
33413561 | |
| Non-small cell lung cancer | Expression of PD-L1 is positively associated with lymph node metastasis and the expression of Ki-67 | 30769852 | |
| Non-small cell lung cancer | The downregulation of PD1 induces the phosphorylation of AKT and ERK1/2 | 32161124 | |
| T lymphoma | PD1+PD-L1+ T lymphoma cells promote tumor growth by activating TCR signaling | 34157461 | |
| Esophageal adenocarcinoma | A single block of PD1 and PD-L1 decrease the expression of DNA repair genes | 35228614 | |
| Oral cancer | The proliferation inhibition of AFE is related to the downregulation of PD-L1 | 30116189 | |
| FGL1 | MC38 colon cancer mouse models | The knockout of FGL1 inhibits the proliferation of cancer cells | 30580966 |
| SGC-7901 gastric cancer cells | The downregulation of FGL1 is correlated with a decrease in vimentin and N-cadherin and an increase in E-cadherin | 29845203 | |
| Lung adenocarcinoma | The downregulation of FGL1 inhibits the proliferation of PC9 and HCC827 cancer cells via MYC pathway | 35399566 | |
| LKB1 mutant A549 lung adenocarcinoma cell line | The downregulation of FGL1 promotes the proliferation and epithelial–mesenchymal transition (EMT) of cancer cell | 31322182 | |
| Pancreatic ductal adenocarcinoma | The downregulation of FGL1 promotes the arrest at the G2/M cell cycle and the expression of Cyclin B1, inhibiting the growth of tumor cells | 33801246 | |
| Hepatocellular carcinoma | Cancer cells grow faster in FGL1-null mice with the activation of Akt and mTOR signal pathways | 26225745 | |
| CD155 | Medulloblastoma | The decrease in MAP4K4 induces the downregulation of CD155 and further inhibits the growth of Medulloblastoma cells | 35296518 |
| B16 melanoma | Emodin inhibits the expression of CD155 and further inhibits the proliferation of tumor cells by inducing cell-cycle G2/M arrest | 31325728 | |
| B16-F10 melanoma | The silencing of CD155 inhibits the growth of tumor cells and activates T cells and NK cells | 33089844 | |
| Hepatocellular carcinoma | The CD155/SRC complex inhibits p38 MAPK signaling pathway and further regulates the proliferation of HCC cells | 35384345 | |
| Cervical cancer | The suppression of CD155 ①activates the apoptosis and autophagy of tumor cells, ②induces G0/G1 cell-cycle arrest ③inhibits the AKT/mTOR/NF-kB signal pathway |
34164340 | |
| CT26 and Sw620 colon cancer | The suppression of CD155 ①inhibits the expression of Cyclin D1 and CDK4, ②induces the arrest of the cell cycle in G1 |
28816021 | |
| Glioma | The silencing of CD155 decreases the expression of Rho A/B, Rho GTPases, and Rac 1/2/3 | 22363471 | |
| CD47/SIRP-α | Prostate cancer | The overexpression of SIRP-α ①induces the apoptosis of prostate cancer cell ②inhibits the activation of NF-κB pathway and p38 mitogen-activated protein kinase ③suppresses the expression of cyclooxygenase-2 (COX-2) |
28588738 |
| Nasopharyngeal carcinoma | The coinhibition of miR-200a and CD47 exerts a more potent inhibition of tumor proliferation than the single-block group | 32149101 | |
| Adamantinomatous craniopharyngioma (APC) | CD47 activates the MAPK/ERK pathway | 35156226 | |
| Colorectal cancer (CRC) | ①CD47 binds with ENO1 and protects it from ubiquitin-mediated degradation ②CD47 induces the phosphorylation of ERK and glycolytic activity of CRC cells |
32226539 | |
| U87 and U373 astrocytoma | CD47 interacst with PLIC-1 and e activates PI3K/Akt pathway | 21125662 | |
| Hepatocellular carcinoma | B6H12 (anti-CD47 mAb) augments the effect of doxorubicin and cisplatin in HCC treatment, inhibiting the macrophage-mediated phagocytosis. | 26351778 | |
| Breast cancer | Anti-CD47 antibody promotes the effect of doxorubicin chemotherapy, inhibiting the growth of tumor cells significantly | 30056566 | |
| CD276 | Oral squamous cell carcinoma (OSCC) | ①CD276 interacts with DC-SIGN with terminal α-galactose and higher fucosylation ②The knockdown of CD276 inhibits tumor growth |
26438868 |
| Oral squamous cell carcinoma (OSCC) | ①CD276 upregulates the expression of HIF-1α via the PI3K/Akt/mTOR pathway, ②CD276 increases the uptake of glucose and enhances the Warburg effect |
31737114 | |
| Hepatocellular carcinoma | The downregulation of CD276 inhibits the expression of MMP2, MMP14, and the activation of MMP2 | 33204103 | |
| Colorectal cancer | miRNA-128 inhibits the expression of CD276, and high levels of CD276 promote tumor growth | 33743142 | |
| Colorectal cancer | CD276 promotes tumor angiogenesis and increases the expression of VEGFA by activating the NF-κB pathway | 31974361 | |
| Acute monocytic leukemia and mantle cell lymphoma | The knockdown of CD276 is related to the decrease in PCNA and Ki67, inducing cell-cycle arrest in G0/G1 phase | 26203263 | |
| MCL Z138 and Maver mantle cell lymphoma | The silencing of CD276 induces an arrest of the G0/G1 phase | 25872657 | |
| Cervical cancer | miRNA-199a targets the 3′-untranslated region of CD276 and regulates its expression, and then activates the AKT/mTOR signaling pathway to inhibit tumor proliferation | 32856542 | |
| Ovarian cancer | CD276 activates the PI3K/AKT signaling pathway through the upregulation of BCL-2 | 31819652 | |
| Lung adenocarcinoma | ELK1 works as a transcription factor that binds to CD276 and regulates its expression, further promoting tumor proliferation and EMT process in the A549 cell line | 30127617 34970415 |
|
| IDO1 | Colorectal cancer | Metabolites from the IDO1–kynurenine pathway induce the activation of the PI3K-Akt signal to enhance the nuclear translocation of β-catenin and promotes CRC proliferation and apoptosis resistance | 30679179 |
| Hepatocellular carcinoma | ①IDO1 induces the activation of Aryl hydrocarbon receptor ②IDO1 activates the Src-PTEN-PI3K/Akt-GSK-3β signal |
34769098 | |
| Colon cancer | The silencing of IDO1 ①inhibits the expression of β-catenin in the nuclears ②inhibits the expression of Axin2 and Cyclin D1 |
23669411 | |
| SIGLEC-15 | MNNG/HOS and 143B osteosarcoma cells | The silencing of SIGLEC-15 induces the decreased expression of dual-specificity phosphatase 1 and the activation of JNK/MAPK and p38/MAPK signals | 34336699 |
| Osteosarcoma | SIGLEC-15 inhibits tumor proliferation by affecting the activity of STAT3/Bcl-2 signaling pathway | 35398779 | |
| TIM3 | Esophageal squamous cell carcinoma | The downregulation of TIM3 ①increases the expression of MMP-9 and E-cadherin ②TIMP-1, vimentin, and N-cadherin decreases ③inhibits the activation of p-Akt, p-GSK-3β, and SNAIL pathways |
27430162 |
| Nasopharyngeal carcinoma | TIM3 exerts proliferation, migration, and invasion regulation, mainly through the SMAD7/SMAD2/SNAIL1 axis | 32184631 | |
| Breast cancer | The overexpression of TIM3 ①induces the upregulation of VEGF, TWIST, MMP1, c-Myc, and Cyclin D1 ②promotes the activation of NF-κB/STAT3 signaling pathway ③induces the downregulation of E-cadeherin |
33223752 | |
| Osteosarcoma | The silencing of TIM3 ①inhibits the activation of NF-κB signals ②decreases the expression of vimentin and SNAIL ③increases the level of NF-κB p65 phosphorylation |
27706678 | |
| U266 and RPMI-8226 myeloma cell lines | The knockdown of TIM3 induces the downregulation of AKT, P13K, mTOR, and NF-κB, resulting in the inhibition of tumor proliferation and increased apoptosis | 33330064 | |
| Galectin-9 | Esophageal adenocarcinoma | The administration of Galectin-9 ①elevates the level of cleaved PARP and cleaved caspase-3/9 ②autophagy markers SQSTM1/p62 and LC3-II are both upregulated ③CDK4, Cyclin D1, and Cyclin E are all decreased |
28586026 |
| Esophageal squamous cell carcinoma | The administration of Galectin-9 inhibits tumor growth by inducing cell apoptosis via activating caspase-3, p38 mitogen-activated protein kinase, and JNK | 31146370 | |
| Cholangiocarcinoma | Galectin-9 induces cell apoptosis and inhibits the proliferation of TFK-1 and HuH-28 cholangiocarcinoma cell lines with an increase in CCK-18 | 26260906 | |
| Colon cancer | ①Galectin-9 upregulates the expression of CCK-18 ②Galectin-9 induces the apoptosis of CACO-2 and CW-2 cells ③Galectin-9 increases the expression of IL-18 and TIMP-2 |
33907832 | |
| Liver metastatic carcinoma from pancreatic cancer cell lines KMP2, KMP7, and KMP8 | The administration of Galectin-9 induces the increase in CCK18, fluorescein isothiocyanate (FITC), cleaved caspase-3, cleaved PARP, caspase-7, Smac/Diablo, HtrA2/Omi, and cytochrome c | 28656219 | |
| Gallbladder carcinoma | The administration of Galectin-9 induces the increase in CCK18 and phosphorylated p53 | 26797414 |