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25th Anniversary of IJMS: Updates and Advances in Molecular Oncology

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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: 31 December 2025 | Viewed by 12907

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Special Issue Editor

Dr. Peter J. K. Kuppen

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Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Interests: colorectal cancer; tumor-immmune interactions; cancer genetics and epigenetics; immunotherapy; biomarkers
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Special Issue Information

Dear Colleagues,

Cancer research entered a new molecular era at the turn of the 21st century: the full sequence of the human genome was just published, and genomic sequencing became standard practice and is now even part of routine clinical diagnostics. Today, as we celebrate the journal’s 25th anniversary, we reflect not only on its growth and accomplishments but also on the remarkable journey of cancer research, which the journal has documented and helped shape. Our understanding of cancer biology has deepened from single-gene models to complex networks involving epigenetics, tumour heterogeneity, the tumour microenvironment, and interactions with the immune system. This has led to whole new cancer treatment options and improved diagnostics, all leading to much better prospects for current cancer patients.

This anniversary Special Issue intends to bring together a collection of articles that reflect on the journal’s legacy while highlighting key advances that are currently redefining the field. We invite long-standing leaders and emerging voices, all of whom share a commitment to rigorous science and translational impact, to contribute to this special issue. Together, these pieces provide both a retrospective lens and a forward-looking perspective on the challenges and opportunities that lie ahead of us.

Among the highlights of this issue are reviews and original studies covering diverse and pressing topics: the evolving role of precision oncology, the promise and limitations of liquid biopsy technologies, advances in cancer immunotherapy, the rise of AI and digital pathology, and novel insights into the molecular mechanisms of tumour development. Each contribution will be selected not only for its scientific merit but also for its relevance to the journal’s mission of connecting the bench and bedside.

We also recognize that the future of molecular oncology demands continued collaboration across disciplines, sectors, and continents. As cancer remains one of the most complex and urgent health challenges of our time, the integration of molecular insights with clinical practice remains as critical today as it was 25 years ago. With this in mind, Molecular Oncology will continue to serve as a platform for work that not only advances knowledge but also catalyses real-world progress.

We invite you to contribute to this Special Issue, reflect on the progress we have made together, and join us in shaping the next 25 years of molecular oncology all for our shared pursuit of better cancer care.

Dr. Peter J. K. Kuppen
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

molecular oncology
cancer epigenetics
tumour heterogeneity
tumour microenvironment
precision oncology
liquid biopsy
cancer immunotherapy

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Published Papers (12 papers)

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Research

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27 pages, 3603 KB

Open AccessArticle

Elacridar Reverses P-gp-Mediated Drug Resistance in Ovarian Cancer Cells in 2D and 3D Culture Models

by Piotr Stasiak, Justyna Sopel, Julia Maria Lipowicz, Agnieszka Anna Rawłuszko-Wieczorek, Karolina Sterzyńska, Jan Korbecki and Radosław Januchowski

Int. J. Mol. Sci. 2025, 26(24), 12105; https://doi.org/10.3390/ijms262412105 - 16 Dec 2025

Viewed by 88

Abstract

Multidrug resistance (MDR) remains a major obstacle in the treatment of ovarian cancer. MDR is often mediated by the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). In this study, we evaluated the ability of elacridar, a dual P-gp and BCRP inhibitor, to overcome MDR in W1, an ovarian cancer cell line sensitive to Paclitaxel (PAC) and its PAC-resistant variants. Cells were cultured under both two-dimensional (2D) and three-dimensional (3D) conditions to account for differences in tumor-like microenvironments. The MDR1 gene and P-gp protein expression were determined for the analyzed model; P-gp activity was measured by flow-cytometry and fluorescent observation, with and without elacridar. The MTT tests were carried out to evaluate how elacridar, combined with chemotherapeutics, affects cell viability. Our results demonstrate that elacridar effectively inhibited transporter activity and increased cellular sensitivity to PAC and DOX. The inhibitory effect was observed in both 2D and 3D cultures, although the re-sensitization effect in 3D conditions was less pronounced, reflecting the complexity of tumor-specific resistance mechanisms. These findings highlight elacridar as a promising compound for reversing MDR in ovarian cancer and emphasize the importance of 3D models in preclinical drug evaluation. Further studies in advanced in vitro and in vivo models are required to assess the potential of elacridar better. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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16 pages, 2090 KB

Open AccessArticle

Bidirectional Mendelian Randomization and Multi-Omics Uncover Causal Serum Metabolites and Neuro-Related Mechanistic Pathways in Acute Myeloid Leukemia

by Haohan Ye, Yuanheng Liu, Jun Tang and Xiaoli Li

Int. J. Mol. Sci. 2025, 26(23), 11307; https://doi.org/10.3390/ijms262311307 - 22 Nov 2025

Viewed by 577

Abstract

Acute myeloid leukemia (AML) is a lethal clonal hematopoietic malignancy. Several reports have shown that serum metabolite alterations have been implicated in AML, but the causal relationship and underlying biological mechanisms remain unclear. We performed bidirectional Mendelian randomization (MR) to evaluate the association between 486 serum metabolites and AML. The analytical approaches used to minimize research bias included the inverse variance weighting (IVW), MR-Egger and weighted median (WM) methods. Sensitivity analyses were performed using Cochran’s Q Test, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Leave-one-out (LOO) analysis. Metabolic pathway analysis was conducted using the MetaboAnalyst 6.0 platform. We utilized RNA-seq data to explore the potential genes and mechanisms underlying the regulation of AML occurrence by serum metabolites. We identified 23 serum metabolites (13 known and 10 unknown) significantly associated with AML. Sensitivity analyses further validated the robustness of these associations. No evidence of reverse causality was detected by reverse MR analysis. The core pathways were histidine metabolism and fructose/mannose metabolism. Transcriptomic integration revealed 39 overlapping genes (differentially expressed genes vs. metabolite-associated genes) as key mediators, enriched in neuroactive ligand signaling, synaptic vesicle cycle, and GABAergic synapse (KEGG), plus synapse assembly and calmodulin binding and neuron-to-neuron synapse (GO). This study establishes causal links between specific serum metabolites and AML, revealing neuro-related mechanistic pathways. These findings provide novel biomarkers and therapeutic targets for AML precision medicine. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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11 pages, 1132 KB

Open AccessArticle

FGFR2 Might Be a Promising Therapeutic Target for Some Solid Tumors: Analysis of 1312 Cancers with FGFR2 Abnormalities

by Hinano Nishikubo, Dongheng Ma, Tomoya Sano, Daiki Imanishi, Takashi Sakuma, Canfeng Fan, Yurie Yamamoto, Motohiro Yamamori and Masakazu Yashiro

Int. J. Mol. Sci. 2025, 26(21), 10777; https://doi.org/10.3390/ijms262110777 - 5 Nov 2025

Viewed by 820

Abstract

Genetic abnormalities of the fibroblast growth factor receptor 2 (FGFR2) gene, including amplification, fusions, and mutations, have been reported in various solid tumors. While molecular targeted therapies against FGFR2 fusion have been proved to be useful in cholangiocarcinoma, the therapeutic significance of FGFR2 inhibitors remains unclear in other various solid cancers. Genomic and clinical information from solid tumor cancer gene panel testing cases is consolidated in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. This study aimed to utilize the C-CAT database to clarify the clinical–pathological significance of FGFR2 abnormalities. A total of 101,231 patients with solid cancer have been registered in the C-CAT database between June 2019 and June 2025. Of the 101,231 cases, 1312 cases with FGFR2 gene abnormalities were analyzed. FGFR2 alterations included amplification in 515 cases, fusion in 280 cases, and mutations in 568 cases. They were detected most frequently in the biliary tract (271 cases), esophagus/stomach (231 cases), and breast (211 cases). Amplification was frequent in the esophagus/stomach (205 cases) and breast (105 cases). Mutations were frequent in the uterus (111 cases), breast (89 cases), and biliary tract (86 cases). Among 515 FGFR2 alteration cases, FGFR2 inhibitors were administered in 85 cases. Of the 85 cases, disease control was achieved in 49 cases, 44 cases of which were biliary tract cancer. FGFR2 might be a promising therapeutic target not only for cholangiocarcinoma with fusion but also for esophagus/stomach cancer and breast cancer with FGFR2 alterations. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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17 pages, 1275 KB

Open AccessArticle

miRNA Signatures in Endometrial Cancer: Implications for Oncogenesis and Polymerase Epsilon (POLE) Mutation Status

by Alexandros Lazaridis, Nikolas Dovrolis, Hector Katifelis, Despoina Myoteri, Iakovos Vlahos, Nikos F. Vlahos and Maria Gazouli

Int. J. Mol. Sci. 2025, 26(21), 10438; https://doi.org/10.3390/ijms262110438 - 27 Oct 2025

Viewed by 813

Abstract

MicroRNAs (miRNAs) are key regulators of gene expression with critical roles in oncogenic signaling. Endometrial cancer (EC) has been redefined with the identification of POLE-ultramutated tumors which, despite their hypermutated phenotype, show more favorable prognosis. We profiled miRNA expression in tumor tissues from forty (40) EC patients and twenty (20) healthy controls using qPCR panels. POLE exonuclease domain mutations (P286R, V411L) were genotyped, and subgroup analyses were conducted between POLE-mutated (n = 7) and POLE-wild-type (n = 33) tumors. Bioinformatic analyses included validated miRNA–mRNA interactions, target enrichment, and Gene Ontology (GO) pathway mapping. Comparison of EC versus healthy endometrium revealed 50 significantly dysregulated (∣log₂ (FoldReg)∣ > 1 and BH FDR < 0.05) miRNAs, including up-regulation of the oncogenic hsa-miR-181a-5p, hsa-miR-23a-3p, hsa-miR-200c-3p, and down-regulation of tumor-suppressive let-7 family members. Target enrichment implicated canonical oncogenic regulators such as MYC, TP53, and VEGFA. POLE-mutated tumor analysis demonstrated a miRNA signature, with 19 miRNAs significantly down-regulated, including let-7f-5p and hsa-miR-200b-3p. Findings for the EC versus healthy endometrium comparison were validated against TCGA-UCEC sequencing data which confirmed concordant dysregulation of key miRNAs across platforms. Our findings reveal that EC is characterized by widespread miRNA deregulation, with a unique global down-regulation signature in POLE-mutated tumors. These results highlight the potential of miRNAs as complementary biomarkers for classification and potential targets in EC. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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22 pages, 3487 KB

Open AccessArticle

Proteomic Profiling of Pre- and Post-Surgery Saliva of Glioblastoma Patients II: A Preliminary Investigation of the Complementary Low Molecular Mass Fraction

by Alexandra Muntiu, Federica Vincenzoni, Diana Valeria Rossetti, Massimo Castagnola, Irene Messana, Federica Iavarone, Andrea Urbani, Giuseppe La Rocca, Alessio Albanese, Alessandro Olivi, Giovanni Sabatino and Claudia Desiderio

Int. J. Mol. Sci. 2025, 26(20), 9995; https://doi.org/10.3390/ijms26209995 - 14 Oct 2025

Viewed by 548

Abstract

This research aimed to analyze the proteomic profile of the low-molecular mass fraction of salivary pools from patients with glioblastoma IDH wild type (GBM) to disclose the small protein and peptide components, including protein fragments, cryptides, and tumor-associated peptides, still lacking specific information in the literature, to the best of our knowledge. This fraction, corresponding to the unretained proteome fraction, was obtained by pretreating the acid-soluble fraction of saliva through Filter-Aided Sample Preparation devices with a filter molecular cutoff of 10 kDa. The fraction was analyzed by LC-MS in its entire form, without trypsin pre-digestion, following a top–down approach. Data from the analysis of pre- and post-operative salivary pools from patients with newly diagnosed and recurrent GBM were compared and discussed with data obtained in our previous study on the complementary salivary proteome fraction > 10 kDa analyzed by a bottom–up approach and data from the literature. The results highlighted a panel of GBM-associated peptide fragments from different protein precursors, namely, ANXA1, CFL1, GLUL, PFN1, H2AC12, ACTB, and HBB, which are suggested for further exploration as potential diagnostic and prognostic biomarkers and clinical applications. These findings, although providing only preliminary results on a small scale, offer new insights into the molecular characteristics of GBM tumor and lay the groundwork for further investigations on a large scale using saliva liquid biopsy for biomarker discovery and validation. The aim is to advance precision medicine and improve clinical outcomes in GBM, one of the most aggressive brain tumors with a poor prognosis, for which early diagnosis and monitoring of treatment response remain significant challenges. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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13 pages, 2011 KB

Open AccessArticle

Parity and NIS Expression in Atypical Cells of Triple-Negative Breast Cancer, and Prognosis

by Grigory Demyashkin, Eugenia Kogan, Tatiana Demura, Anastasia Guzik, Dmitriy Belokopytov, Maxim Batov, Vladimir Shchekin, Irina Bicherova, Petr Shegai and Andrei Kaprin

Int. J. Mol. Sci. 2025, 26(20), 9947; https://doi.org/10.3390/ijms26209947 - 13 Oct 2025

Cited by 1 | Viewed by 520 | Correction

Abstract

Breast cancer is one of the most common malignancies worldwide, affecting 2.3 million and causing 670,000 deaths in women annually. However, data indicate that the risk of developing breast cancer decreases with pregnancy at a young age, and each subsequent pregnancy further reduces the risk by approximately 10%. One of the characteristics inherent in both the mammary gland epithelium in pregnant women and luminal epithelial adenocarcinomas is the increased expression of NIS—the sodium/iodide symporter, whose defective cytoplasmic forms possess pro-oncogenic properties. Therefore, the analysis of the degree of influence of pregnancy on NIS expression in breast cancer cells is of medical interest. The aim of this study is to conduct a comparative morphological analysis of NIS expression in breast cancer cells according to the number of pregnancies of each patient. This study included 161 patients with triple-negative breast cancer who visited the P.A. Herzen Moscow Oncology Research Institute from 2020 to 2023. Immunohistochemical examination was performed using antibodies to NIS. The gravidity status of women was determined based on provided medical documentation. The degree of NIS expression was assessed using a modified Gainor scale. Statistical analysis was performed using mean and standard deviation (SD) depending on the normality of the distribution (Lilliefors test: p > 0.20); a p-value ≤ 0.05 was considered statistically significant. The degree of correlation between variables was assessed using Kendall’s tau rank correlation coefficient. A weak to moderate negative correlation (τ: −0.369) was found between the number of pregnancies and the degree of NIS expression in triple-negative breast cancer cells. In patients with triple-negative breast cancer, a weak to moderate negative correlation was found between the degree of NIS expression and gravidity status. The discovered phenomenon is likely due to the terminal differentiation of the mammary gland epithelium that occurs during pregnancy. This may potentially indicate the suppression of pro-oncogenic properties of atypical cells developed from the epithelium that has undergone terminal differentiation. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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17 pages, 5865 KB

Open AccessArticle

Detection of Targetable Genetic Abnormalities in Neuroblastoma Circulating Tumour DNA

by Marina Danilenko, Sharanya Nath, Jack Baines, Freya Gordon, Swathi Merugu, Lisa M. Allinson, Aaron Potts, Bethany Collins, Angharad Goodman, Samuel E. Kidman, Ciaron McAnulty, David Jamieson and Deborah A. Tweddle

Int. J. Mol. Sci. 2025, 26(19), 9466; https://doi.org/10.3390/ijms26199466 - 27 Sep 2025

Viewed by 1103

Abstract

Neuroblastoma (NB) is an aggressive childhood cancer requiring intensive multimodal therapies in high-risk (HRNB) patients. Currently, invasive surgical biopsies are required to classify NB risk group and assign treatment based on the tumour genetic profile. Circulating tumour DNA (ctDNA) obtained from blood samples can be used to identify tumour biomarkers. Here we applied targeted next-generation sequencing (tNGS) using a panel of 42 genes to analyse 32 NB ctDNA samples for the presence of single-nucleotide variants and copy number changes from 28 patients in all NB risk groups. In two additional ctDNA samples, droplet digital PCR was used to detect hotspot ALK variants. Pathogenic mutations with a variant allele frequency (VAF) > 1% were identified in 13/32 (41%) ctDNA samples. ALK and PTPN11 were the most frequent, each being detected in 4/32 (13%) samples, together with oncogene amplifications. Targeted NGS of ctDNA detected actionable variants, including those absent in the diagnostic primary tumour due to spatial and temporal heterogeneity. Our findings confirm the usefulness of ctDNA in detecting genetic abnormalities in NB. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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16 pages, 3324 KB

Open AccessArticle

The Role of MICA/B Molecules and the NKG2D Receptor in the Interaction Between NK-92 Cells and JEG-3 Cells

by Elizaveta Tyshchuk, Elizaveta Denisova, Polina Grebenkina, Marina Pereviazkina, Anastasia Stolbovaya, Ilya Smirnov, Olga Shashkova, Irina Gryazeva, Lidiya Terekhina and Dmitry Sokolov

Int. J. Mol. Sci. 2025, 26(17), 8400; https://doi.org/10.3390/ijms26178400 - 29 Aug 2025

Viewed by 1175

Abstract

MICA/B molecules (MICs) are stress-induced molecules expressed by infected and tumor cells. Their expression also characterizes trophoblast cells. Cytotoxic lymphocytes, including natural killer (NK) cells, express the NKG2D receptor, aiding them in the recognition and destruction of target cells that present MICs. To evade destruction, target cells employ various defense mechanisms, including the secretion of soluble forms of MICs. Choriocarcinoma JEG-3 cells and NK-92 cells were used to assess the expression of MICs and NKG2D. The cytotoxicity of NK-92 cells against JEG-3 cells in the presence of trichostatin A (TSA), anti-MICA/B antibodies (anti-MICA/B), and recombinant MIC proteins (rMICA/B) was evaluated. JEG-3 cells and NK-92 cells express MICs. Additionally, NK-92 cells exhibit high levels of NKG2D receptor expression. TSA treatment reduced the surface expression of MICs on choriocarcinoma cells, and was also associated with the release of soluble MICB. However, the TSA-induced decrease in MIC expression by choriocarcinoma cells did not protect them from the cytotoxic effects of NK cells. Only the activation of NK cells by IL-12 resulted in a decline in susceptibility of TSA-treated choriocarcinoma cells to NK cell-mediated cytotoxicity. Thus, NK cells activated by IL-12 lose their ability to effectively kill TSA-treated choriocarcinoma cells through the MIC-mediated mechanisms. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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Review

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16 pages, 512 KB

Open AccessReview

CAR-T in the Treatment of Solid Tumors—A Review of Current Research and Future Perspectives

by Natalia Picheta, Julia Piekarz, Karolina Daniłowska, Katarzyna Szklener and Sławomir Mańdziuk

Int. J. Mol. Sci. 2025, 26(19), 9486; https://doi.org/10.3390/ijms26199486 - 28 Sep 2025

Viewed by 3117

Abstract

The aim of this narrative review is to present the current state of knowledge regarding the use of chimeric antigen receptor T-cell (CAR-T) therapy in solid tumors. Phase I clinical trials and side effects are discussed. The review is based on an analysis of available scientific publications, primarily phase I trials, Food and Drug Administration (FDA) reports, and PubMed, Scopus, and Google Scholar sources. It includes clinical trials and review articles from 2016 to 2025. Accumulated data indicate promising efficacy of CAR-T therapy in the treatment of certain solid tumors, particularly those of the gastrointestinal tract, although clinical responses were often limited to disease stabilization. The therapy was generally well tolerated, with a low incidence of serious adverse events. Efficacy was found to depend on factors such as the type of target antigen, the presence of conditioning therapy, and the ability to overcome the immunosuppressive tumor microenvironment. CAR-T therapy remains experimental outside of hematological malignancies, but further development, refinement of receptor design, and the search for better molecular targets may make it an effective treatment option for solid tumors as well. Current studies are in early phase and require confirmation in larger-scale randomized trials. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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18 pages, 946 KB

Open AccessReview

TIGIT Expression and Its Implications in Non-Small-Cell Lung Cancer Progression and Therapy: A Systematic Review

by Julia Piekarz, Natalia Picheta, Katarzyna Szklener and Sławomir Mańdziuk

Int. J. Mol. Sci. 2025, 26(19), 9307; https://doi.org/10.3390/ijms26199307 - 23 Sep 2025

Viewed by 1621

Abstract

Lung cancer (LC) is the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) representing 85–90% of cases. Despite the efficacy of PD-1/PD-L1 immune checkpoint inhibitors, primary and acquired resistance highlight the need for novel immunotherapeutic strategies. A systematic review of the literature from 2020 to 2025 was conducted according to the PICO model. Six studies were included, encompassing phase I–III clinical trials. The analysis focused on efficacy, safety, and emerging therapeutic strategies targeting TIGIT in NSCLC. TIGIT blockade enhances cytotoxic T lymphocyte and natural killer (NK) cell activity, strengthening antitumor immunity. Clinical trials, particularly with the monoclonal antibody tiragolumab combined with PD-1/PD-L1 inhibitors, show promising synergistic effects. Emerging strategies, including bispecific antibodies (e.g., TIGIT/PD-1 and TIGIT/PD-L1) and experimental cell therapies, are under investigation to further improve the antitumor response. Anti-TIGIT therapies represent a highly promising approach in NSCLC. While phase III data remain limited, biomarker-driven, well-designed trials are essential. If validated, TIGIT blockade could become a key addition to immuno-oncology treatment strategies for NSCLC. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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36 pages, 3285 KB

Open AccessReview

Cold, Hot, and Lethal—The Tumour Microenvironment and the Immunology of Head and Neck Squamous Cell Carcinoma

by Svatava Vyhnánková, Lukáš Lacina, Martin Chovanec, Jan Plzák, Karel Smetana, Jr., Jiří Netušil, Michal Kolář and Radek Šindelka

Int. J. Mol. Sci. 2025, 26(18), 8844; https://doi.org/10.3390/ijms26188844 - 11 Sep 2025

Viewed by 1944

Abstract

Head and neck squamous cell carcinomas (HNSCCs) represent a diverse group of malignancies, both clinically and biologically, with human papillomavirus (HPV) infection playing a significant role. HPV-positive tumours generally tend to have a better prognosis and are driven by oncoproteins E6 and E7. In contrast, HPV-negative tumours typically have a worse prognosis and are often linked to mutations in tumour suppressor genes. HNSCCs exist within a complex environment known as the tumour microenvironment (TME). The TME includes tumour cells, cancer stem cells (CSCs), cancer-associated fibroblasts (CAFs), immune cells, extracellular matrix (ECM), blood vessels, and various signalling molecules. These components support tumour progression, invasion, metastasis, and resistance to treatment. Intercellular signalling within the TME—mediated by cytokines such as IL-6, TGF-b, and galectins—further promotes tumour growth and systemic effects like cachexia. Notably, the TME shares features with granulation tissue during wound healing, supporting the concept of cancer as a chronic, non-resolving wound. Effective therapy must target not only tumour cells but also the dynamic TME. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Oncology)

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