Tumor Microenvironment in Melanoma—Characteristic and Clinical Implications
Abstract
1. Introduction
2. Melanoma Microenvironment—Characteristic and Clinical Implications
2.1. Cancer-Associated Fibroblasts/Melanoma-Associated Fibroblasts (CAFs)
2.2. Tumor-Associated Macrophages (TAMs)
2.3. Tumor-Infiltrating Lymphocytes (TILs)
2.3.1. B-Cells
2.3.2. CD4+ T-Cells
2.3.3. CD8+ T-Cells
2.3.4. Tregs
2.4. Dendritic Cells (DCs)
3. Therapeutic Implications and Future Perspectives
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ACTA2 | Actin alpha cardiac muscle 2 |
ADAM9 | ADAM metallopeptidase domain 9 |
ARID5A | AT-rich interactive domain 5A |
αSMA | Alpha smooth muscle actin |
Bcl-XL | B-cell lymphoma-extra large |
BIRC3 | Baculoviral IAP repeat containing 3 |
BDCA1 | Blood dendritic cell antigen 1 |
BDCA3 | Blood dendritic cell antigen 3 |
BTLA | B- and T-lymphocyte attenuator |
CAFs | Cancer-associated fibroblasts |
cDC | Conventional dendritic cell |
cDC1 | Conventional dendritic cell type 1 |
cDC2 | Conventional dendritic cell type 2 |
CD103 | Cluster of differentiation 103 |
CD107a | Cluster of differentiation 107a |
CD11c | Cluster of differentiation 11c |
CD141 | Cluster of differentiation 141 |
CD19 | Cluster of differentiation 19 |
CD25 | Cluster of differentiation 25 |
CD5 | Cluster of differentiation 5 |
CD80 | Cluster of differentiation 80 |
CD90 | Cluster of differentiation 90 |
CD206 | Cluster of differentiation 206 |
CCR1 | C-C motif chemokine receptor 1 |
CCR2 | C-C motif chemokine receptor 2 |
CCR7 | C-C motif chemokine receptor 7 |
CXCL16 | C-X-C motif chemokine ligand 16 |
CXCL9 | C-X-C motif chemokine ligand 9 |
CXCL12 | C-X-C motif chemokine ligand 12 |
CXCR3 | C-X-C motif chemokine receptor 3 |
CXCR5 | C-X-C motif chemokine receptor 5 |
DNGR-1 | Dendritic cell natural killer receptor-1 |
EOMES | Eomesodermin |
FCεR1 | High-affinity immunoglobulin epsilon receptor 1 |
FLT3L | Fms-like tyrosine kinase 3 ligand |
FAP | Fibroblast-activation protein |
FOXP3 | Forkhead box P3 |
GNLY | Granulysin |
GM-CSF | Granulocyte-macrophage colony-stimulating factor |
ICOS-L | Inducible co-stimulator ligand |
ILT7 | Immunoglobulin-like transcript 7 |
IFN-γ | Interferon gamma |
IFNγ | Interferon gamma |
IL-1β | Interleukin-1 beta |
IL-6 | Interleukin-6 |
IL-8 | Interleukin-8 |
IL-10 | Interleukin-10 |
IL-15 | Interleukin-15 |
IL-12 | Interleukin-12 |
IL-17 | Interleukin-17 |
ID2 | Inhibitor of DNA-binding 2 |
IDO | Indoleamine 2,3-dioxygenase |
IDO1 | Indoleamine 2,3-dioxygenase 1 |
IRF1 | Interferon regulatory factor 1 |
IRF4 | Interferon regulatory factor 4 |
IRF8 | Interferon regulatory factor 8 |
IRF9 | Interferon regulatory factor 9 |
KCNJ8 | Potassium channel, inwardly rectifying subfamily J member 8 |
LAMP-1 | Lysosomal-associated membrane protein 1 |
LAMP3 | Lysosomal-associated membrane protein 3 |
LIPSTIC | Liposome-based short interfering RNA delivery technology for immunocellular targeting |
MMP1 | Matrix metalloproteinase 1 |
MMP3 | Matrix metalloproteinase 3 |
MMPs | Matrix metalloproteinases |
MRC1 | Mannose receptor C-type 1 |
MARCKSL1 | Myristoylated alanine-rich C-kinase substrate-like 1 |
MZB1 | Marginal zone B-cell marker 1 |
NKG7 | Natural killer cell granule protein 7 |
NK | Natural killer cells |
OX40 | Ox40 receptor |
PD-1 | Programmed cell death protein 1 |
PD-L1 | Programmed cell death ligand 1 |
PD-L2 | Programmed cell death ligand 2 |
PRDM1 | PR domain containing 1 |
RELB | RelB proto-oncogene |
RGS5 | Regulator of G-protein signaling 5 |
RUNX3 | Runt-related transcription factor 3 |
SDF-1 | Stromal-derived factor 1 |
STAT1 | Signal transducer and activator of transcription 1 |
STAT3 | Signal transducer and activator of transcription 3 |
T-bet | T-box transcription factor |
TCR | T-cell receptor |
TILs | Tumor-infiltrating lymphocytes |
TLR4 | Toll-like receptor 4 |
TLR7 | Toll-like receptor 7 |
TLR9 | Toll-like receptor 9 |
TLS | Tumor lymphoid structures |
TNF | Tumor necrosis factor |
TNF-α | Tumor necrosis factor alpha |
TME | Tumor microenvironment |
TWIST1 | Twist family bHLH transcription factor 1 |
TWIST2 | Twist family bHLH transcription factor 2 |
XCL1 | C-X-C motif chemokine ligand 1 |
XCL2 | C-X-C motif chemokine ligand 2 |
XCR1 | C-X-C motif chemokine receptor 1 |
ZEB2 | Zinc finger E-box binding homeobox 2 |
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Analyzed Feature | CAFs | Refs. | TAMs | Ref. | TILs | Refs. | DCs | Refs. |
---|---|---|---|---|---|---|---|---|
Origin | Resident fibroblasts, BM-MSCs, EMT, EndMT, MMT, adipocytes, pericytes | [25] | TRMs—derived from yolk sac and fetal liver BM-derived monocytes—from myeloid progenitors in the bone marrow | [40,41,42,43] | Recruited from the population of circulating lymphocytes | [50] | CDP-derived, MDP-derived, lymph node-derived, epidermis-derived | [79,81,82,83,85] |
Activation mechanisms | Exosomes secreted by cancer cells, IL-1β, IL-6, IL-8, TGF-β, PDGF, FGF-2, miR-211/155 | [34] | Lactate, exosomes secreted by cancer cells, TCIPA (CCL2, IL-1α/β, SDF-1), CCL8, CCL15 | [28,29,47,48] | IFN-γ/IL-2/IL-4/IL-6/IL-21/TGF-β, antigen presentation by DC, interaction with MHC-I/MHC-II | [54,60,65,72] | XCL1, CCL5, FLT3L, TLR7, TLR9, tissue damage, contact with T-cells, CD40–CD40L interaction, CTLA-4/PD-1 blockade, IL-27 | [79,82,83,84,87] |
Markers | mCAFs: COL1A1, COL1A2, COL3A1, LUM, POSTN, TNC; iCAFs: MMP1, MMP3, IL6, CXCL8, IDO1; myoCAFs: ACTA2, COL1A1, RGS5, KCNJ8, MCAM; other markers: FSP-1, vimentin, FAP, podoplanin, PDGFR α/β, decorin, osteonectin, desmin, CD90/THY1, NG2 | [34,36] | M1: TNF-α, IL-1β, IL-6, iNOS, CD80; M2: Arg1, Chi3l3, MRC1, CD206 | [44] | T: CD3; Th: CD4; Treg: FOXP3, CD25; cytotoxic: CD4, EOMES, TBET, RUNX3/CD8 degranulation: GNLY, NKG7, CD107a; tumor-reactive profile: CD39/CD103, PD-1, TIGIT, CXCL13; B: CD20, CD23/CD69/CXCR4/TCL1A/MKI67 (subtype dependent); plasma cells: PRDM1, XBP1, MZB1, SSR4 | [51,54,59,60,65,67,72] | cDC1: XCR1, DNGR-1, CLEC9A, CD103, BDCA3, CD141 cDC2: BDCA1, CD1c, CD11c, CD5, FCεR1, CCR2, BTLA LCs: CD83, IDO1 pDCs: BDCA-2, ILT7, TRAIL, Granzyme B, ICOS-L, IDO, PD-L1 mregDCs: LAMP3, CCR7, CD83, BIRC3, MARCKSL1, PD-L1, CD200, Clusterin DC3s: FcγRIIB/III | [79,81,82,83,84,85,87] |
Functions | ECM remodeling, physical barrier for immune cells, production of immunosuppressive cytokines, promotion of cancer cell migration and invasiveness | [5,34,36] | Phagocytosis and antigen presentation, promotion of angiogenesis (VEGF, TGF-β, and IL-10), potential support of primary tumor development (TRMs) and metastasis (M2), facilitation of immunosuppression (PD-L1) | [40,42,45,47,48] | B: a crucial component of TLS, antigen processing, antibody production; T: cytotoxicity (cytotoxic CD4+/CD8+), recruitment and stimulation of immune cells (Th), induction of tolerance, adenosine secretion(Treg) | [54,59,60,65,70,72] | Antigen uptake, presentation, cross-presentation, migration, chemokine/cytokine secretion, T-cell activation, immune regulation, cytotoxicity (TRAIL/granzyme B), Treg induction, costimulatory/inhibitory molecule expression | [79,81,82,83,84,87] |
Subpopulations | mCAFs, iCAFs, myoCAFs, ucCAFs | [36] | M0, M1, M2, F4/80^high, F4/80^low | [43,44] | B:Naive, CXCR4+, Follicular, Germinal center, Plasma; T: Th1, Th2, Th17, (n/i/o/x)Tregs, cytotoxic CD4+/CD8+ | [51,54,59,60,65,70,72] | cDC1, cDC2, pDC, LCs, mregDC, DC3 | [79,82,83,84,85] |
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Sikorski, H.; Żmijewski, M.A.; Piotrowska, A. Tumor Microenvironment in Melanoma—Characteristic and Clinical Implications. Int. J. Mol. Sci. 2025, 26, 6778. https://doi.org/10.3390/ijms26146778
Sikorski H, Żmijewski MA, Piotrowska A. Tumor Microenvironment in Melanoma—Characteristic and Clinical Implications. International Journal of Molecular Sciences. 2025; 26(14):6778. https://doi.org/10.3390/ijms26146778
Chicago/Turabian StyleSikorski, Hubert, Michał Aleksander Żmijewski, and Anna Piotrowska. 2025. "Tumor Microenvironment in Melanoma—Characteristic and Clinical Implications" International Journal of Molecular Sciences 26, no. 14: 6778. https://doi.org/10.3390/ijms26146778
APA StyleSikorski, H., Żmijewski, M. A., & Piotrowska, A. (2025). Tumor Microenvironment in Melanoma—Characteristic and Clinical Implications. International Journal of Molecular Sciences, 26(14), 6778. https://doi.org/10.3390/ijms26146778