Table 1.
Tumor microenvironment components
| Components | Classification | Molecular characteristics | Function in TME | Major Role | |
|---|---|---|---|---|---|
| Immune cells | |||||
| T lymphocytes | |||||
| CD8+ T cell | TME & TIME | CD3+CD8+ | Cytotoxicity | Anti-tumoral | |
| Th1 cell | TME & TIME | CCR6+CXCR3+ | Production of IL-2 and IFN-γ | CD8+ T cell supporting | Anti-tumoral |
| Th2 cell | TME & TIME | Production of IL-4, IL-5 and IL-13 | B cell responses supporting | Pro-tumoral | |
| Th17 cell | TME & TIME | Production of IL-17A, IL-17F, IL-21, IL-22 | Angiogenesis, tumorigenesis, immune regulation | Ambiguous | |
| Treg cell | TME & TIME | CD4+FOXP3+CD25+ | Immune suppression | Pro-tumoral | |
| B lymphocytes | TME & TIME | CD19+CD20+CD138+ | Antibody production, antigen presentation, TLSs formation | Anti-tumoral | |
| Innate lymphoid cell (ILCs) | |||||
| ILC1s | |||||
| NK cells | TME & TIME | Expression of T-bet; Eomes+ CD27− | Cytotoxic functions without prior sensitization | Anti-tumoral | |
| Non-NK cells | TME & TIME | Expression of T-bet; Eomes− CD27+ | Secretion of IFN-γ and TNF-α to induce tumor dependent anti-tumor immune responses | Ambiguous | |
| ILC2s | TME & TIME | Expression of GATA3; secretion of type 2 cytokines | Secretion of IL-5, IL-13, IL-4 to inhibit anti-tumor immunity | Pro-tumoral | |
| ILC3s | TME & TIME | Expression of RORγt | Heterogeneous cells secreting various cytokines and chemokines | Ambiguous | |
| Tumor-associated macrophages | HLA-DR+CD68+ CD11c− | ||||
| M1 | TME & TIME | CD86+ CD80+ iNOS+ | Promoting anti-tumor TH1 and TH17 immune responses | Anti-tumoral | |
| M2 | TME & TIME | CD163+CD206+ | Supporting angiogenesis, tumor progression, and metastasis; immune suppression | Pro-tumoral | |
| MDSCs | TME & TIME | CD11b+HLA-DR− | Differentiating into TAMs, immune suppression | Pro-tumoral | |
| Dendritic cells | TME & TIME | Siglec-H+CD317+ | Binary immune regulatory function shaped by TME | Ambiguous | |
| Neutrophils | CD14+HLA-DR+CD206−CD86− | ||||
| N1 | TME & TIME | Supported by TGF-β and G-CSF | Immune respond initiation, antigen presenting | Anti-tumoral | |
| N2 | TME & TIME | Supported by IFN-γ and hepatocyte growth factor | Remodeling ECM, promoting angiogenesis and tumor growth | Pro-tumoral | |
| Stromal cells | |||||
| Cancer-associated fibroblasts | TME | Cellular markers: α-SMA, FAP-α, FSP-1/S100A4, PDGFRβ | Promoting tumor cell proliferation and invasion, angiogenesis; ECM remodeling; bidirectional immune regulation | Pro-tumoral | |
| Endothelia cells | TME | Cellular markers: CD31; consisting of blood vessels | Angiogenesis, tumor metastasis | Pro-tumoral | |
| Pericytes | TME | Cellular markers: Calponin, CD90, DLK, NG2, PDGF-A, SMA | Promote primary tumor growth, negative regulator of metastasis, | Pro-tumoral | |
| Adipocytes | TME | Cellular markers: CD34 | Secretion of hormones, metabolites, growth factors, enzymes and cytokines | Pro-tumoral | |
| Mesenchymal stem cells | TME | Cellular markers: CD105, CD90, CD117, CD133 | Forming the premetastatic niche; promoting tumor initiation and progression | Pro-tumoral | |
| Vessels | |||||
| Blood vessel | TME | Tubular structures formed by endothelial cells (cellular markers: CD31) | Promoting metastasis and angiogenesis, | Pro-tumoral | |
| Lymph vessel | TME | Tubular structures formed by lymphatic endothelial cells (cellular markers: LYVE-1, Podoplanin, PROX1, VEGFR-3) | Foster tumor metastasis, physical link between lymph nodes and tumor | Pro-tumoral | |
| Extracellular matrix | |||||
| Collagen, fibronectin, elastin, laminin | TME | Complex noncellular three-dimensional macromolecular network | Physical scaffold for cell, tumor cell dissemination, depot for cytokines and growth factors | Pro-tumoral | |
| Matrix metalloproteases, Cathepsins | TME | Enzymes secreted and activated by malignant cells in extracellular matrix | ECM remodeling, aiding metastasis, angiogenesis and inflammation | Pro-tumoral | |
| Immune molecules | |||||
| Cytokines | TME & TIME | Mainly secreted by immune cells; acting in a paracrine, autocrine or endocrine manner | Promoting leukocyte growth, survival and activation; promoting tumor immunogenicity, tumor cell proliferation, angiogenesis | Ambiguous, mainly anti-tumoral | |
| Chemokines | TME & TIME | Regulation of cell movement and leukocyte attractants | Promoting tumor cell migration, invasion and metastasis; promoting immune cell migration, maturation | Ambiguous, mainly anti-tumoral | |
| Extracellular nonspecific chemicals | |||||
| Oxygen | TME | Aerobic cellular respiration | Favor immunosuppressive phenotypes | Ambiguous | |
| Amino acids | TME | Components and substrates for various critical processes in cell metabolism and physiology | Supporting physiological processes of both tumor and immune cells, immune regulation | Ambiguous | |
| Glucose | TME | Major source of energy for cells | TME dependent influence of energy metabolism in both immune and tumor cells | Ambiguous | |
| Lactate | TME | Products of glycolysis | Inhibiting anti-tumor immunity, decrease the pH within the TME | Pro-tumoral | |
| Carbon dioxide | TME | Products of oxidative phosphorylation | Causing tumor tissue acidosis | Ambiguous | |
| Fatty acids | TME | Involvement in biological progression and cell structure | Heterogeneous consequences for different cells, leading to immunosuppressive effects | Ambiguous | |
| Metal ions | TME | Involvement in biological progression | Regulating tumor and immune cells | Ambiguous | |
TME, tumor microenvironment; TIME, tumor immune microenvironment; MDSCs, myeloid-derived suppressor cells; TLSs, tertiary lymphoid structures