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Tumor Microenvironment and Cancer Progression: Molecular Insights for Targeted Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 September 2025 | Viewed by 2857

Special Issue Editor


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Guest Editor
Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA
Interests: apoptosis; epigenetics; DNA; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A better understanding of the complex ecosystem of dynamically interacting cancer, non-malignant cells, and the extracellular matrix (ECM) which create the tumor microenvironment (TME) has significantly impacted cancer research.

This field has made impressive strides in illuminating the diverse cell populations within tumors and the interactions between them and with the ECM, discovering mechanisms of immune response modulation and detecting how the TME supports metabolic changes reprogrammed by tumors and enhances tumor progression. Continuously improving tumor models helps researchers understand TME interactions in a more clinically relevant context and evaluate new treatments. One critical challenge is effectively targeting the diverse subpopulations of cells within a tumor, including those that contribute to resistance. Understanding the dynamic interplay between various cell types, signaling pathways, and extracellular matrix components in different tumor types and stages is an ongoing issue.

In this Special Issue, we aim to collect high-quality research papers addressing the complexity of TME interactions, tumor heterogeneity, the development of biomarkers guiding personalized treatment, resistance to therapies targeting the TME or in which the TME is involved, immune editing, and tumor evolution.

Dr. Tetiana Zaǐchuk
Guest Editor

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Keywords

  • tumor microenvironment
  • immune response modulation
  • signaling pathways
  • extracellular matrix components
  • tumor evolution

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Published Papers (3 papers)

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Research

18 pages, 3187 KiB  
Article
Real-World Evaluation of Microsatellite Instability Detection via Targeted NGS Panels in Routine Molecular Diagnostics
by Petra Škerl, Vesna Vogrič, Vida Stegel, Vita Šetrajčič Dragoš, Olga Blatnik, Gašper Klančar and Srdjan Novaković
Int. J. Mol. Sci. 2025, 26(15), 7138; https://doi.org/10.3390/ijms26157138 - 24 Jul 2025
Viewed by 254
Abstract
Microsatellite instability (MSI) is a clinically important biomarker for predicting responses to immune checkpoint inhibitors and identifying individuals with Lynch syndrome. Although MSI detection has been incorporated into Illumina’s next-generation tumor sequencing workflows, interpretation of the results remains challenging due to the absence [...] Read more.
Microsatellite instability (MSI) is a clinically important biomarker for predicting responses to immune checkpoint inhibitors and identifying individuals with Lynch syndrome. Although MSI detection has been incorporated into Illumina’s next-generation tumor sequencing workflows, interpretation of the results remains challenging due to the absence of standardized thresholds and reporting criteria. In this retrospective study, we assessed the performance of MSI detection using Illumina’s targeted NGS panels—TruSight Tumor 170 and TruSight Oncology 500. The NGS-based MSI results were compared to those obtained by the reference method, MSI-PCR, across multiple tumor types in a real-world cohort of 331 cancer patients. The NGS method demonstrated high concordance overall (AUC = 0.922), though sensitivity was lower in colorectal cancers (AUC = 0.867) due to broader score variability and overlapping distributions. Our findings support the clinical utility of Illumina’s NGS-derived MSI scores for identifying MSI-H tumors, with a recommended MSI score cut-off value of ≥13.8%. Additionally, a borderline group was introduced, defined by an MSI score ranging from ≥8.7% to <13.8%. Within this range, the integration of TMB into the MSI classification workflow significantly improves diagnostic accuracy. For samples that remain inconclusive, orthogonal confirmation using MSI-PCR is advised to ensure accurate MSI classification. Full article
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18 pages, 2859 KiB  
Article
Effect of IL-1β on NSCLC-Derived Small Extracellular Vesicles as Actors in Mediating Cancer Progression and Evading Immune System
by Hamid Heydari Sheikhhossein, Luisa Amato, Viviana De Rosa, Caterina De Rosa, Annalisa Ariano, Sabrina Critelli, Daniela Omodei, Valeria Nele, Concetta Tuccillo, Paola Franco, Giovanni N. Roviello, Rosa Camerlingo, Adriano Piattelli, Giovanni Vicidomini, Floriana Morgillo, Giuseppe De Rosa, Maria Patrizia Stoppelli, Carminia Maria Della Corte, Natalia Di Pietro and Francesca Iommelli
Int. J. Mol. Sci. 2025, 26(14), 6825; https://doi.org/10.3390/ijms26146825 - 16 Jul 2025
Viewed by 314
Abstract
Background: Increased IL-1β levels may promote carcinogenesis and metastasis by affecting tumor biology and the tumor microenvironment (TME). In this context, extracellular vesicles (EVs) play a key role in cell-to-cell communication, thus modulating the TME and immune response. Here, we aimed to test [...] Read more.
Background: Increased IL-1β levels may promote carcinogenesis and metastasis by affecting tumor biology and the tumor microenvironment (TME). In this context, extracellular vesicles (EVs) play a key role in cell-to-cell communication, thus modulating the TME and immune response. Here, we aimed to test whether tumor-derived small EVs (TEVs) isolated from sensitive and osimertinib-resistant (OR) non-small-cell lung cancer (NSCLC) cells may promote EMT via fibronectin binding to α5β1 integrin as well as suppress the immune system and if these effects may be favored by IL-1β. Methods: TEVs were isolated from control, OR, and IL-1β-stimulated NSCLC cells. Expressions of fibronectin and PD-L1 were screened in TEVs and the mRNA levels of vimentin and SMAD3 were also assessed in cancer cells after TEV co-culturing. Furthermore, to detect the effect on immune cells, we co-cultured TEVs with lung cancer patients’ peripheral blood mononuclear cells (PBMCs). Results: TEVs were positive for fibronectin and the highest protein levels were found in TEVs obtained from the OR and IL-1β-stimulated cells. TEV-mediated activation of α5β1 signaling led to the upregulation of vimentin and SMAD3 mRNA in NSCLC cells and stimulated cell migration. EVs also increased PD-1, CTLA-4, FOXP3, TNF-α, IL-12, and INF-γ mRNA in lung cancer patients’ immune cells. Conclusions: Our findings indicate that TEVs promote EMT in NSCLC cells by the activation of the fibronectin–α5β1 axis. Finally, IL-1β stimulation induces TEV release with biological properties similar to OR TEVs, thus leading to cancer invasion and immune suppression and suggesting that inflammation can promote tumor spreading. Full article
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14 pages, 11359 KiB  
Article
Unveiling Biomarkers in Head and Neck Squamous Cell Carcinoma through Bioinformatics: The Role of SPP1 and KRT78
by Jaehwan Cheon, Byoungjae Kim, Jaehyung Park, Jaemin Shin and Tae Hoon Kim
Int. J. Mol. Sci. 2024, 25(22), 12062; https://doi.org/10.3390/ijms252212062 - 10 Nov 2024
Cited by 1 | Viewed by 1891
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the most common form of head and neck cancer, ranking sixth in global cancer incidence. Identifying molecular drivers of tumorigenesis and metastasis is essential for early detection and treatment. This study analyzed gene expression profiles [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is the most common form of head and neck cancer, ranking sixth in global cancer incidence. Identifying molecular drivers of tumorigenesis and metastasis is essential for early detection and treatment. This study analyzed gene expression profiles from three datasets (GSE6791, GSE29330, and GSE58911) to identify differentially expressed genes (DEGs) in HNSCC. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were employed to functionally annotate these DEGs. A protein–protein interaction (PPI) network was constructed for selecting hub genes using the STRING database. Finally, hub gene and protein expression levels were evaluated in patients with HNSCC, along with their association with overall survival. Our analysis identified twenty-eight co-DEGs comprising eight up-regulated and twenty down-regulated genes, primarily involved in extracellular matrix (ECM) organization, proteolysis, ECM disassembly, and keratinization processes. Furthermore, the PPI network revealed eight hub genes based on their high degree of connectivity. Notably, SPP1 demonstrated up-regulation, while KRT78 was down-regulated in HNSCC. Remarkably, the expression levels of these hub genes correlated with tumor grade, clinical cancer stage, and poor prognosis in HNSCC. Our findings hold significant clinical potential for early diagnosis and the development of novel therapeutic targets for patients with HNSCC. Full article
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