Microenvironment and Tumor Heterogeneity as Pharmacological Targets in Precision Oncology
Abstract
1. Introduction
2. The Tumor Microenvironment: A Complex Pharmacological Target for Precision Medicine
2.1. Tumor Heterogeneity
2.2. Intratumoral Heterogeneity (ITH): Clonal Evolutionary and the Cancer Stem Cell (CSCs) Models
2.3. The Importance of the Tumor Microenvironment (TME)
2.4. Mesenchymal Stem Cells (MSCs)
2.5. Tumor-Associated Fibroblasts (CAFs)
2.6. Vascular and Immune Components of the TME
3. Therapeutic Opportunities Offered by Precision Medicine
3.1. Precise Cancer Treatment Definition, Biomarkers, Targets, Types and Scope
- Replacement of the mutated tumor-suppressor gene with a normal gene to restore its function,
- Inhibition of the expression of one specific oncogene,
- Stimulation of the immune response,
- Inhibition of angiogenetic processes,
- Sensitization of cancer cells to other cancer treatments, and
- Modulation of the TME.
3.2. Tumor Microenvironment Targets
3.3. Liquid Biopsy
3.4. Critical Issues and Limitations in Actual Precise Medicine Strategies
3.5. Translational Insights and Emerging Therapeutic Technologies: From Bench-to-Bedside
4. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADC | Antibody–Drug Conjugates |
ADCC | Antibody–Dependent Cell-mediated Cytotoxicity |
ADCP | Antibody–Dependent Cellular Phagocytosis |
APC | Antigen-Presenting Cell |
CAF | Cancer-Associated Fibroblast |
CDC | Complement-Dependent Cytotoxicity |
CAN | Copy Number Alteration |
CRISPR | Clustered Regularly Interspaced Short Palindromic Repeats |
CSC | Cancer Stem Cell |
CTC | Circulating Tumor Cell |
cfDNA | Circulating cell-free DNA |
ctDNA | circulating tumor DNA |
EMA | European Medicines Agency |
EMT | Epithelial–Mesenchymal Transition |
FDA | Food and Drug Administration |
HIF | Hypoxia-Inducible Factor 1 |
HRE | Hypoxia-Responsive Elements |
IFN | Interferon |
THE | Interleukin |
ITH | Intratumor Heterogeneity |
mAb | Monoclonal Antibody |
MMP | Matrix Metalloproteinase |
MDSC | Myeloid-Derived Suppressor Cell |
MSC | Mesenchymal Stem Cell |
NGS | Next Generation Sequencing |
NFkB | Nuclear Factor kappa B |
NK | Natural Killer |
PDGF | Platelet-Derived Growth Factor |
PGF | Placental Growth Factor |
SDF-1 | Stromal Cell-Derived Factor 1 |
TAM | Tumor-Associated Macrophage |
TGF | Tumor Growth Factor |
TLR | Toll-Like Receptor |
TME | Tumor Microenvironment |
TNF | Tumor Necrosis Factor |
Treg | T regulatory cell |
VCAM-1 | Vascular Cellular Adhesion Molecule-1 |
VEGF | Vascular Endothelial Growth Factor |
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Name of the Active Principle (Drug) | Mechanism of Action | Clinical Applications |
---|---|---|
Imatinib | BCR-ABL tyrosine kinase (TK) inhibitor | Treatment of chronic myeloid leukemia and gastrointestinal stromal tumors |
Sorafenib | Multiple TK inhibitor | Treatment of unresectable liver carcinoma, advanced renal carcinoma, and differentiated thyroid carcinoma |
Gefitinib | Blocks epidermal growth factor receptor TK | Treatment of non-small-cell lung cancer NSCLC |
Vandetanib | Selective inhibitor of RET kinase | Treatment against the growth and spread of cancers related to the activation of RET oncogene, like medullary thyroid cancer and some NSCLC |
Name of the Active Principle (Drug) | Mechanism of Action | Clinical Applications |
---|---|---|
Nivolumab and pembrolizumab | Bind and block programmed death-1 (PD-1) protein on T lymphocytes | Treatment of melanoma, non-small-cell lung cancer (NSCLC), kidney cancer, Hodgkin’s lymphoma, malignant pleural mesothelioma, bladder cancer, esophageal and stomach cancer |
Cetuximab | Blocks the epidermal growth factor receptor (EGFR) | Treatment of metastatic colorectal and head and neck cancers that have a normal KRAS gene |
Panitumumab | Blocks the epidermal growth factor receptor | Treatment of colorectal cancers that have a normal KRAS gene |
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Tonello, S.; Rolla, R.; Tillio, P.A.; Sainaghi, P.P.; Colangelo, D. Microenvironment and Tumor Heterogeneity as Pharmacological Targets in Precision Oncology. Pharmaceuticals 2025, 18, 915. https://doi.org/10.3390/ph18060915
Tonello S, Rolla R, Tillio PA, Sainaghi PP, Colangelo D. Microenvironment and Tumor Heterogeneity as Pharmacological Targets in Precision Oncology. Pharmaceuticals. 2025; 18(6):915. https://doi.org/10.3390/ph18060915
Chicago/Turabian StyleTonello, Stelvio, Roberta Rolla, Paolo Amedeo Tillio, Pier Paolo Sainaghi, and Donato Colangelo. 2025. "Microenvironment and Tumor Heterogeneity as Pharmacological Targets in Precision Oncology" Pharmaceuticals 18, no. 6: 915. https://doi.org/10.3390/ph18060915
APA StyleTonello, S., Rolla, R., Tillio, P. A., Sainaghi, P. P., & Colangelo, D. (2025). Microenvironment and Tumor Heterogeneity as Pharmacological Targets in Precision Oncology. Pharmaceuticals, 18(6), 915. https://doi.org/10.3390/ph18060915