Table 2.
Research progress of targeting GAMs in the treatment of GBM.
| GAMs targets | Inhibitors | Medication regimen | Research progress | References |
|---|---|---|---|---|
| CSF-1R | BLZ945 | Monotherapy | Promote mouse xenograft model survival, regress established tumor, and decreased M2 markers expression | (129) |
| PLX 3397 | Monotherapy | PLX3397 decreased GAMs accumulation and invasiveness GBM cells in mouse models, slowed tumor growth in mouse models. PLX3397 was well tolerated, readily crossed the BBB but showed no efficacy in GBM patients | (131, 132) | |
| PLX3397 | PLX3397 + vatalanib/dovitinib (tyrosine kinase inhibitors) | PLX2397 inhibits CSF1R phosphorylation, abrogates GAMs M2-polarization, promoting vatalanib and dovitinib therapy efficacy | (130) | |
| BLZ945 | BLZ945+0S1906 (IGF-1R inhibitor) | BLZ945 monotherapy promotes drug resistance via IGF-1R induced PI3K activation, Synergistic use of BLZ945 and 0S1906 prolonged mouse models survival | (134, 135) | |
| PLX 3397 | PLX3397+ IR | IR increased CSF-1R ligand expression and increased CD11b BMDMs in the tumors. PLX3397 both depleted CD11b+ cells and sensitized intracranial tumors to IR | (93) | |
| BLZ945 | BLZ945+IR | Combined treatment is more effective than either therapy alone in GBM mouse models, and delays glioma relapse | (116, 137) | |
| Chemokines | Lentivirus | sh-CXCR4 + pLenti-anti-miR-21 | Double-Targeted Knockdown of miR-21 and CXCR4 Inhibited Malignant Glioma Progression via downregulating PI3K/AKT and Raf/MEK/ERK Pathways | (140) |
| Peptide R | Monotherapy | Peptide R targeting CXCR4 reduced tumor cellularity in vitro, promoted M1 features of GAMs and astrogliosis in orthotopic mouse models | (141) | |
| SB225002 | SB225002 (CXCR2 inhibitor) + TMZ | SB225002 inhibits tumor angiogenesis and Infiltration of GAMs, enhanced anti-tumoral effects were observed after combi-therapy with TMZ | (143, 144) | |
| CNT0888 | CNT0888 (CCL2 monoclonal antibodies) +TMZ | CNT0888 promotes mouse models survival via decreasing GAMs and MDSCs, CNT0888 enhanced TMZ efficacy after co-administration | (145) | |
| CCX872 | CCX872 (CCR2 antagoist) + PD-1 Inhibitor | CCX872 promotes mouse models survival via decreasing MDSCs, CCX872 enhanced anti-PD-1 efficacy after co-administration | (146) | |
| CXCR4 antagoist | CXCR4 antagoist + PD-1 inhibitor | Co-administration showed significant survival benefit than anti-PD-1 monotherapy, decreased MDSCs and GAMs accumulation in the mouse models | (147) | |
| VEGF/VEGFR | Bevacizumab | Monotherapy | Bevacizumab improved radiographic response and clinical benefit to GBM patients, but showed no advantage in PSF compared with historical controls | (148) |
| Bevacizumab | Bevacizumab + sh /recombinant MIF | Bevacizumab monotherapy reduces MIF expression, drives GAMs recruitment and M2-polariztion, mediating therapy resistance | (92) | |
| Bevacizumab, sunitinib | Bevacizumab/sunitinib + PRX17561(CXCR4 inhibitor) | Co-administration of PRX177561 with bevacizumab/sunitinib inhibited tumor growth and reduced the inflammation, increased efficacy of bevacizumab/sunitinib | (142) | |
| Bevacizumab | Bevacizumab + OLA-PEG (SDF-I inhibitor) | Combination therapy significantly promotes GBM mouse models survival compare with bevacizumab monotherapy, OLA-PEG decreased M2-GAMs accumulation | (149) | |
| Cediranib | Cediranib + MEDI3617 (Ang-2 antibody) | Dual anti-VEGFR/Ang-2 therapy extends survival, improves vessel normalization, alters GAMs polarization to M1-type compared with cediranib monotherapy | (150) | |
| PD-1/PDL-1 | Nivolumab | Monotherapy | Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration, but no significant clinical benefit. Nivolumab induce apoptosis of microglia through antibody-dependent cellular cytotoxicity | (152, 153) |
| PD-L1 antibody | PD-L1 antibody +LY2228820 (p38 MAPK inhibitor) | Combination therapy effectively prolongs the survivals of TMZ-resistant GBM-bearing hosts, reduces the accumulation of BMDMs and PD-L1 abundances of BRM | (154) | |
| Nivolumab | Nivolumab +BGB324 (AXL inhibitor) | Nivolumab treatment increased intratumoral GAMs accumulation and AXL activation. Combinatorial therapy effectively prolonged the survival of GBM mouse models | (118) | |
| Nivolumab | Nivolumab + BLZ945 (CSF-1R inhibitor) | BLZ945 ablates CD163+ M2-GAMs and strengthened CD154+CD8+ Tell functionality and GBM apoptosis, enhancing Nivolumab efficacy | (155) | |
| ICIs | ICIs + IL-6 antibody & CD40 agonist | IL-6 neutralization and CD40 stimulation synergistically reduces GAMs-mediated immune suppression and enhances T-cell infiltration and activation in GBM, sensitizes GBM to immune checkpoint blockade | (156) | |
| CRISPR/Cas9 | dual-sgRNAs + HDR template | PD-L1 deletion by gene-editing system increases TNF- α and decreases IL-4 secretions, repolarizes GAMs to M1 phenotype, inhibiting GBM progression. | (157) | |
| Other drugs | CHA | Monotherapy | CHA treatment increased MI markers (INOS, MHC II, CD11c) expression and reduced M2 markers (Arg, 032061 expression, inhibiting tumor cells growth | (158) |
| RQ | Rapamycin (R)+ hydroxychloroquine (Q) | RQ treatment decreased M2-polarization, increased the phagocytic ability and lipid droplets accumulation. Enhanced the intra-tumoral M1 /M2 ratio | (159) | |
| TG100-105 | TG100-105 + TMZ | TG100-105 inhibited IL-11 induced STAT3-MYC signaling pathway activation, decreased GAMs accumulation, and enhanced TMZ efficacy | (88) | |
| Liposomes/ Nanomaterials |
Regorafenib | Disulfiram/copper complex | The albumin nanoparticles modified with dual ligands efficiently passed through the BBB and achieving biomimetic delivery to glioma and GAMs, inhibited the glioma cell proliferation and reprogrammed M2-GAMs to M1 phenotype. | (162) |
| IRF5, IKK β | Nanoparticles | The nanoparticles formulated with mRNAs encoding IL-5 and IKK β reverse the immunosuppressive, tumor-supporting state of GAMs and reprogram them to M1 phenotype that induces anti-tumor immunity and promotes tumor regression | (163) | |
| Simvastatin, fenretinide | TPGS-TAT-embedded lactoferrin nanoparticle | Lactoferrin nanoparticles repolarize GAM from M2 phenotype to M1 by modulating STAT6 pathway and induce ROS-mediated mitochondrial/ apoptosis by inhibiting Ras/Raf/p-Erk pathway in glioma cells | (164) | |
| PQDEA, IL-12 plasmid | APEG-LPs/pIL12 | APEG-LPs/pIL12 transfected GAMs and tumor cells to produce IL12 and converted M2 GAMs to M1 type, recruited T cells and NK cells, and reduced the Tregs population, leading to antitumor effect and prolonging mouse models survival | (165) | |
| HNK, DSF / Cu | CDX-LIPO | CDX-LIPO activates tumor-infiltrating macrophages and dendritic cells, promotes M1-polarization leading to antitumor immunity and tumor regression. CDX-LIPO promotes mTOR-mediated reprogramming of glucose metabolism in gliomas | (166) |