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Review
. 2021 Mar 15;40(1):97.
doi: 10.1186/s13046-021-01893-y.

Underlying mechanisms and drug intervention strategies for the tumour microenvironment

Haoze Li  1   2 , Lihong Zhou  1   2 , Jing Zhou  1   2 , Qi Li  3   4 , Qing Ji  5   6
Affiliations
Review

Underlying mechanisms and drug intervention strategies for the tumour microenvironment

Haoze Li et al. J Exp Clin Cancer Res. .

Abstract

Cancer occurs in a complex tissue environment, and its progression depends largely on the tumour microenvironment (TME). The TME has a highly complex and comprehensive system accompanied by dynamic changes and special biological characteristics, such as hypoxia, nutrient deficiency, inflammation, immunosuppression and cytokine production. In addition, a large number of cancer-associated biomolecules and signalling pathways are involved in the above bioprocesses. This paper reviews our understanding of the TME and describes its biological and molecular characterization in different stages of cancer development. Furthermore, we discuss in detail the intervention strategies for the critical points of the TME, including chemotherapy, targeted therapy, immunotherapy, natural products from traditional Chinese medicine, combined drug therapy, etc., providing a scientific basis for cancer therapy from the perspective of key molecular targets in the TME.

Keywords: Cancer development; Drug intervention strategies; Molecular targets; TME.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Multiple stages of the TME in cancer progression. (I) TME in the budding stage of primary cancer: Oncogene activation leads to the conversion of normal cells to cancer cells, accompanied by the initial microenvironment formation in primary cancer sites containing fibroblasts, immune cells, vascular endothelial cells (VECs), etc. (II) TME in the progressing stage of primary cancer: inflammatory cells (producing chemokines and cytokines), neutrophils, tumour-associated macrophages (TAMs, producing carcinogenic proteases, cytokines and growth factors, and angiogenic factors), VECs, cancer-associated fibroblasts (CAFs, producing vascular endothelial growth factor, VEGF), extracellular matrix (ECM), etc. (III) Pre-metastatic niche: macrophages, platelets, mesenchymal stem cells, bone marrow-derived dendritic cells (BMDCs), immune cells (producing inflammatory cytokines, growth factors and angiogenic factors), etc. (IV) Metastatic niche: myeloid-derived suppressor cells (MDSCs, producing tissue factors and anti-inflammatory cytokines), Treg cells (producing anti-inflammatory cytokines), CAFs (producing transforming growth factor-1), etc.
Fig. 2
Fig. 2
Intervention of chemotherapy on the TME. Neoadjuvant chemotherapy can increase the density of myeloid suppressor cells. Oxaliplatin (OXP) can increase cancer infiltration and activation of CD8+ T cells and reduce cancer CD11b+F4/80high macrophages and spleen MDSCs. PG545 inhibits growth factor-mediated cell invasion, reduces the HB-EGF-induced phosphorylation of AKT, EGFR and ERK, and reduces the cancer burden. Gemcitabine (GEM) or paclitaxel (PTX) inhibited the EMT by reducing the frequency of CTCs and the logarithm of CTCs. Fludarabine has high selectivity for cells with low expression of X-inactivated specific transcription (XIST) and inhibits the growth of brain cancer cells
Fig. 3
Fig. 3
Intervention of targeted therapy on the TME. Regorafenib inhibits the interaction between mesenchymal stem cells (MSCs) and cancer cells. Rapamycin-mediated autophagy can reduce the expression of Bcl-2 and survivin and increase the expression of Smac in TAMS. Apatinib can reduce cancer angiogenesis and inhibit the expression of PD-L1 through targeted STAT3 inhibition of the EMT and blockade of the PI3K/AKT and VEGFR2/RAF/MEK/ERK signalling pathways, thus affecting VEGF-mediated cell proliferation and invasion. WRG-28 inhibits cancer invasion and migration by targeting DDR2. Dasatinib reduced the M2 polarization of TAMS. Bortezomib (BTZ) and phenobarbital (PST) can reduce the survival rate of CAFs and inhibit the proliferation of cancer cells by inducing caspase-3-mediated apoptosis. The inhibition of apelin can inhibit angiogenesis and growth, and reduce the infiltration of suppressor cells derived from the polymorphonuclear myeloid system
Fig. 4
Fig. 4
Intervention of immunotherapy on the TME. Anti-CTLA-4 antibody consumes regulatory T cells and removes Tregs. The use of transforming growth factor-β (TGF-β) inhibitors and anti-PD-L1 antibodies can reduce the TGF-β signal and promote the infiltration of T cells into the cancer centre. Plerixafor inhibits CXCR4 and reduces cancer spread and angiogenesis. Embelin can regulate the cancer-immune microenvironment by increasing the infiltration of Th1 cells, NK cells, CTLs, γδT cells and NKT cells, reducing the infiltration of Th17, PMN-MDSCs, and IL-8- and IL-6-positive immune cells. Anti-c-FMS antibody affects the establishment of breast cancer cells in bone
Fig. 5
Fig. 5
Intervention of the nanoparticle-based drug delivery system in the TME. Functionalized micellar endothelial cells (FucOMDs) adhere to cancer cells and reverse the abnormal expression of several key marker proteins in the pre-metastatic niche. A new type of cancer matrix-targeted nanocarrier (FH-SSL-Nav) can remove CAFs. Photoimmunotherapy (nano-PIT) selectively kills CAFs and increases the invasiveness of T cells. Interferon gene-activated nanoparticle stimulator (STINNP) enhances the cytoplasmic delivery of cyclic guanosine monophosphate-adenosine monophosphate (CGAMP) through an in vivo escape mechanism, activating STING and triggering T cells
Fig. 6
Fig. 6
Intervention of natural products from traditional Chinese medicine on the TME. Curcumin inhibits VEGF, IL-6 and cancer stem cells in vivo and in vitro. Ginsenoside Rh2 (G-Rh2) can regulate the phenotype of TAMs to improve the TME. Dihydrodiosgenin (DYDIO) can inhibit platelet activation and reduce endothelial cell-derived factor VIII (FVIII). Cordycepin can target CSCs and upregulate the apoptosis of cancer cells. Shikonin reduces cancer-derived exosomes to inhibit the spread of breast cancer cell lines. Wogonin inhibits the transformation of EMT into the epithelial stroma by interfering with the IL-6/STAT3 signalling pathway. Sophoridine can inhibit macrophage-mediated immunosuppression through the TLR4/IRF3 pathway and then upregulate the killing effect of CD8+ T cells on gastric cancer. Salvianolic acid A can block the secretion of glucose-regulated protein 78 (GRP78) and inhibit angiogenesis. Triptolide (TP) inhibits the proliferation of cancer cells. Berberine can mediate the transforming growth factor-β signalling pathway, thus inhibiting EMT and promoting apoptosis
Fig. 7
Fig. 7
Intervention of combined drugs on the TME. Rapamycin (RapA) is a mTOR inhibitor that inhibits tumour proliferation through anti-angiogenesis and can be enhanced in combination with cisplatin. Cisplatin combined with paclitaxel inhibits tumour invasion. The combination of everolimus and sunitinib can affect stromal cells and cancer cells in the TME. Antiangiogenic drugs (AADs) combined with carnitine palmitoyltransferase 1A (CPT1) inhibitors significantly inhibited fatty acid oxidation (FAO) -induced cell proliferation and angiogenesis. Ginsenoside Rg3 combined with cisplatin can inhibit epithelial-mesenchymal transition (EMT) of tumour cells. Hedgehog (HH) signalling pathway inhibitors combined with bufalin can inhibit tumour proliferation. Tranilast can dow-regulate CAF activity, promote vascular normalization, and help docetaxel micelles (DTX-ms) reach tumour tissue through veins and kill tumour cells. Sorafenib combined with bufalin affects the tumour vascular microenvironment through targeting the mTOR/VEGF signalling pathway
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