Table 1.
Preclinical studies that target the tumor microenvironment.
| Immune cell(s) | Agent(s) | Target(s) | Model(s) | Effect(s) | Reference(s) |
|---|---|---|---|---|---|
| Tregs | Docetaxel | NA | In vitro | Docetaxel-based chemotherapy decreased Treg after four cycles of treatment | 67 |
| Anti-CD25 antibody | CD25 | LLC model | Deplete Tregs; inhibit tumor growth when combined with radiation; increase the effector T cells | 68 | |
| Anti-CD25 antibody | CD25 | MC38 and EO771 model; LL/2 and 4T1 model | Deplete Tregs; the antitumor effect was associated with CD8+ T and NK cell infiltration level | 69 | |
| Nb-Fc1B0 (CCR8 antibody) | CCR8 | LLC-OVA model | Deplete CCR8+ Tregs; inhibit tumor growth when combined with anti-PD1 | 70 | |
| DCs | Anti-CD40 agonist antibody | CD40 | LLC model | Induce E-cadherin+ inflammatory DCs; enhance antitumor immunity; limit the tumor growth | 76 |
| Macrophages | Targeting specific markers on marcophages | ||||
| Anti-MARCO antibody | MARCO | In vitro | Recover cytolytic activity of NK cells and T cells | 78 | |
| TD-92 | CSF-1R | LLC model | Decrease the expression of CSF-1R on macrophages; inhibit tumor growth combined with PD-1 | 79 | |
| CSF-1R inhibitor | CSF-1R | KrasG12D/+; p53 −/− NSCLC model | Improve the efficacy of anti-angiogenic blockade and ICB | 81 | |
| SIRPα-Fc | SIRPα/CD47 signaling | LLC model | Sensitize the tumor to VEGF blockade | 83 | |
| Reprogramming of macrophages | |||||
| SHP099 | SHP-2 | 344SQ NSCLC adenocarcinoma | Repolarization of M2 TAMs to the antitumor M1 phenotype; triple therapy with radiation and anti-PD-L1 significantly inhibits the primary tumor growth | 85 | |
| Anti-LILRB2 antibody | LILRB2 | LLC model | Enhance TNF-α release; combination of PD-L1 and LILRB2 significantly reduces tumor size | 88 | |
| Anlotinib | VEGFR, FGFR, PDGFR, and c-kit | LLC model | Expand M1-like TAM; inhibit tumor growth when combined with αPD-1 | 87 | |
| MDSCs | CXCR1/2 inhibition | CXCR1/2 | KP mouse model | Deplete the subsets of gMDSCs; combination with SHP099 further inhibits tumor growth with anti-PD-1 | 92 |
| ATRA | NA | LKB1-deficient murine models | Suppress the percentage and function of gMDSCs; inhibit tumor growth when combined with anti-PD-1 | 93 | |
| ARG1/2 inhibitor | ARG1 | KrasG12D lung cancer model | Inhibit the function of MDSC; inhibit tumor growth and enhance T cell numbers and function | 94 | |
ARG1: Arginase 1; ATRA: All-trans retinoic acid; CCR8: C-C chemokine receptor type 8; CSF-1R: Colony-stimulating factor 1 receptor; CXCR1/2: C-X-C motif chemokine receptor 1/2; DC: Dendritic cells; FGFR: Fibroblast growth factor receptor; gMDSC: Granulocytic MDSC; ICB: Immune checkpoint blockade; KP: KrasG12D/+ and p53−/−; LKB1: Liver kinase B1; LILRB2: Leukocyte immunoglobulin-like receptor subfamily B member 2; LLC: Lewis lung cancer; LLC-OVA: LLC-ovalbumin; LILRB2: Leukocyte immunoglobulin-like receptor subfamily B member 2; MARCO: Macrophage receptor with collagenous structure; MDSC: Myeloid-derived suppressor cells; NA: Not available; NK: Natural killer; NSCLC: Non-small cell lung cancer; PD-1: Programed death-1; PDGFR: Platelet-derived growth factor receptor; PD-L1: Programmed death-ligand 1; SHP-2: Src homology-2 domain-containing protein tyrosine phosphatase-2; SIRPα: Signal regulatory protein α; TAMs: Tumor-associated macrophages; TNF-α: Tumor necrosis factor-α; Tregs: Regulatory T cells; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.