Tumor Microenvironment: An Emerging Landscape for Lung Cancer Therapy
Abstract
1. Introduction
2. Tumor-Infiltrating Immune Cells
2.1. Tumor-Infiltrating Lymphocytes (TIL)
Cytotoxic CD8+ T Lymphocytes
3. Tumor Expressing Cytokines
4. Lung Tumor Microenvironment
5. Cells of the Stroma
5.1. Fibroblast Cells
5.2. Immune Cells
5.2.1. T Cells
5.2.2. Macrophage
5.2.3. Mast Cells
5.2.4. Dendritic Cells
5.2.5. Vascular Cell
6. Extracellular Molecules
6.1. Cytokines
6.2. Growth Factors
6.3. Matrix Metalloproteinase
7. Immune Regulation by Stroma
8. Hypoxia and Tumor Microenvironment
9. Role of microRNAs in Regulating the Tumor Microenvironment
10. Role of Cells in the Tumor Microenvironment
11. The Antitumor Properties of Natural Extracts and Phytochemicals Against Lung Cancer
12. Therapeutic Strategies and Challenges in Modulating the Tumor Microenvironment in Lung Cancer
13. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
NSCLC | Non-small cell lung cancer |
SCLC | Small cell lung cancer |
TME | Tumor microenvironment |
ICB | Immune checkpoint blockade |
MSCs | Mesenchymal stromal/stem cells |
TAFs | Tumor-associated fibroblasts |
Tregs | Regulatory T cells |
MDSCs | Myeloid-derived suppressor cells |
NK | Natural killer cells |
DCs | Dendritic cells |
ECM | Extracellular matrix |
HIFs | Hypoxia-inducible factors |
MMPs | Matrix metalloproteinases |
MHC | Major histocompatibility complex |
ICI | Immune checkpoint inhibitors |
TIL | Tumor-infiltrating lymphocyte |
CAFs | Cancer-associated fibroblasts |
MDSCs | Myeloid-derived suppressor cells |
TAMs | Tumor-associated macrophages |
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Immune Cell Type | Main Function in TME | Clinical/Prognostic Association |
---|---|---|
CD8+ T cells | Cytotoxic killing of tumor cells | Improved survival, better ICI response [19,20] |
CD4+ T cells | Helper/regulatory roles; coordinate immune responses | Variable; subset-dependent [20,21] |
Regulatory T-cells (Tregs) | inhibit anti-tumor immunity | Poorer prognosis [20,22] |
B cells | Antibody production, antigen presentation | Mixed; high density may predict HPD [19,23] |
Macrophages (M1/M2) | M1: pro-inflammatory/anti-tumor; M2: immunosuppressive | M1: favorable; M2: poor prognosis [20,21,22] |
Myeloid-derived suppressor cells (MDSCs) | Inhibit T-cell function, promote tumor growth | Poorer prognosis [20] |
Natural Killer cells (NKs) | Direct killing of tumor cells (innate immunity) | Generally favorable [21] |
Dendritic cells (DCs) | Antigen presentation, T-cell activation | It can be immunosuppressive in TME [22] |
Mast cells | Modulate inflammation, angiogenesis | Prognostic value in LUAD [21] |
Cytokine | Primary Source | Susceptible Cells | Primary Function |
---|---|---|---|
IL-1 | Macrophages, monocytes, fibroblasts | Endothelium, hypothalamus, T/B cells | Co-stimulation, inflammation, fever |
IL-2 | T cells, NK cells | T/B/NK cells, monocytes | Growth and activation of immune cells |
IL-4 | T cells | T/B cells | Th2 differentiation, IgE switching |
IL-6 | Macrophages, T cells | T/B cells, liver | Acute phase response, inflammation |
IL-10 | Th2 cells | Macrophages, T cells | Anti-inflammatory, suppresses APCs |
IL-12 | NK cells, macrophages | T cells | Promotes Th1 differentiation |
IL-17 | NKT cells, ILCs | Epithelial, endothelial cells | Inflammation, infection control |
IL-21 | CD4+ T cells, NKT cells | T/B/NK cells | Enhances immune responses |
IL-23 | APCs | T cells, NK cells | Promotes chronic inflammation via Th17 |
IFN-γ | T, NK, NKT cells | Monocytes, endothelial cells | MHC upregulation, macrophage induction |
TNF-α | T cells, macrophages | Immune, endothelial, liver cells | Inflammation, fever, acute-phase response |
TGF-β | T cells, macrophages | T cells | Suppresses immune activation |
IL-35 | Tregs | T cells | Immunosuppressive, induces iTr35 |
IL-37 | DCs, Monocyte | Macrophages, B cells | Dampens excessive inflammation |
Cytokine | Source | Functions |
---|---|---|
IL-6 | T cells, adipocytes, macrophages | Proinflammatory action, promotes differentiation and cytokine production |
IL-8 | Macrophages, epithelial cells, endothelial cells. | Proinflammatory action, promotes angiogenesis and chemotaxis |
IL-10 | Monocytes, B cells, T cells | Anti-inflammatory action, inhibits proinflammatory cytokines |
IL-17 | Th17 cells | Proinflammatory action, enhances cytokine and chemokine production, contributes to antitumor immunity |
IL-27 | Antigen-presenting cells (APCs) | Anti-inflammatory action, induces IL-10 production |
IL-35 | Regulatory T cells (Tregs) | Anti-inflammatory action, promotes Treg proliferation, suppresses Th17 cells |
IL-37 | NK cells, monocytes, epithelial cells, B cells | Anti-inflammatory, antimicrobial, and contributes to antitumor immunity |
TNF-α | Macrophages, CD4+ lymphocytes, adipocytes, NK cells | Proinflammatory action, induces cell proliferation, cytokine production, and apoptosis |
IFN-γ | NK cells, T cells | Antiviral and proinflammatory action |
TGF-β | T cells, macrophages | Anti-inflammatory action, suppresses proinflammatory cytokine production |
Granulocyte-macrophage colony-stimulating factor (GM-CSF) | T cells, macrophages, fibroblasts | Proinflammatory action, enhances neutrophil and monocyte function, activates macrophages |
Vascular endothelial growth factor (VEGF) | Macrophages, endothelial cells, platelets | Promotes vasculogenesis, angiogenesis, endothelial chemotaxis, and migration |
microRNA | Targets | Expression Status (Underexpressed/Overexpressed/ Unchanged) | Comments (If Any) | Reference |
---|---|---|---|---|
miR-487b | SUZ12,BM11, MYC | Overexpressed | Tumor suppressor | Xi et al., 2013 [165] |
miR-449 | HDAC1 | Overexpressed | AM Rusek et al., 2015 [166] | |
miR-101 | EZH2 | Overexpressed | AM Rusek et al., 2015 [166] | |
miR-486 | IGF1R | Underexpressed | NSCLC tumor suppressor | C M. Croce et al., 2013 [167] |
miR-9 | MHC 1 gene | Overexpressed | AM Rusek et al., 2015 [166] | |
miR-124a | CDK6 | Overexpressed | Tumor suppressor | A Lujambio et al., 2007 [168] |
miR-221 | TIMP3 | Overexpressed | AM Rusek et al., 2015 [166] | |
miR-222 | TIMP3 | Overexpressed | AM Rusek et al., 2015 [166] | |
miR-429 | ZEB1/2 | Overexpressed | NSCLC oncogenic | Wu Cl et al., 2018 [169] |
miR-128b | EGFR in NSCLC | Underexpressed | Tumor suppressor | Becker-Santos DD et al., 2012 [170] |
miR-1827 | SK-LU-1, RBX1 in NSCLC | Underexpressed | NSCLC tumor suppressor | SM Noor et al., 2018 [171] |
miR-378 | RBX1, CRKL in NSCLC | Overexpressed | NSCLC tumor suppressor | SM Noor et al., 2018 [171] |
miR-630 | Mut-Bcl-2–3′-UTR | Unchanged | NSCLC tumor suppressor | Huei Lee et al., 2018 [172] |
miR-31 | LATS2/PPP2R2A | Overexpressed | NSCLC oncogenic | Liu et al., 2010 [173] |
miR-221/222 | PUMA | Overexpressed | NSCLC oncogenic | Zhang et al., 2010 [174] |
miR-197 | PD-L1 | Overexpressed | NSCLC oncogenic | Fujita et al., 2015 [175] |
microRNA-146a | EGFR | Overexpressed | NSCLC tumor suppressor | Chen et al., 2013 [176] |
Cell Types | In the Progression of Lung Cancer | In the Induction of the EMT Process | In the Development of Anticancer Drugs Resistance |
---|---|---|---|
Tumor-infiltrating lymphocytes (TILs) | Positive correlation and high levels are associated with better overall survival [24,177] | Induce epithelial–mesenchymal transition (EMT) [178] | Resistance to anti-tumor immunity [179] |
Cancer-associated fibroblasts (CAFs) | Enhancing the plasticity and self-renewal capabilities of CSCs [58] | Induce epithelial–mesenchymal transition (EMT) [180] | Support cancer cell survival in the presence of anticancer drugs [181] |
Mesenchymal stem cells (MSCs) | Promote tumor metastasis and tumorigenesis [182] | Induce epithelial–mesenchymal transition (EMT) [182] | Play a significant role in cancer progression and drug resistance [183] |
Tumor endothelial cells (TECs) | Cancer progression by supporting angiogenesis and metastasis [184] | Crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) [185] | Contribute to drug resistance in cancer therapy [186] |
Regulatory T cells (Tregs) | Interact with cancer stem cells (CSCs) and contribute to tumor relapse [187] | Promote epithelial-mesenchymal transition (EMT) [188] | Play a crucial role in cancer treatment resistance [189] |
Tumor-associated macrophages (TAMs) | Support cancer stem cells (CSCs) and promotes lung cancer progression [190] | Induce epithelial–mesenchymal transition (EMT) [191] | Promote drug resistance in cancer treatment [192] |
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Sohag, S.M.; Toma, S.N.; Imon, M.A.-I.; Maihemuti, M.; Ahmed, F.; Mimi, M.A.; Mahmud, I.; Hasan, M.M. Tumor Microenvironment: An Emerging Landscape for Lung Cancer Therapy. Future Pharmacol. 2025, 5, 34. https://doi.org/10.3390/futurepharmacol5030034
Sohag SM, Toma SN, Imon MA-I, Maihemuti M, Ahmed F, Mimi MA, Mahmud I, Hasan MM. Tumor Microenvironment: An Emerging Landscape for Lung Cancer Therapy. Future Pharmacology. 2025; 5(3):34. https://doi.org/10.3390/futurepharmacol5030034
Chicago/Turabian StyleSohag, S. M., Sharmin Nur Toma, Md. Al-Imran Imon, Maiweilan Maihemuti, Famim Ahmed, Mst. Afsana Mimi, Imran Mahmud, and Md. Mahmudul Hasan. 2025. "Tumor Microenvironment: An Emerging Landscape for Lung Cancer Therapy" Future Pharmacology 5, no. 3: 34. https://doi.org/10.3390/futurepharmacol5030034
APA StyleSohag, S. M., Toma, S. N., Imon, M. A.-I., Maihemuti, M., Ahmed, F., Mimi, M. A., Mahmud, I., & Hasan, M. M. (2025). Tumor Microenvironment: An Emerging Landscape for Lung Cancer Therapy. Future Pharmacology, 5(3), 34. https://doi.org/10.3390/futurepharmacol5030034