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Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition

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A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 10565

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Dr. Ming-Wei Lin

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Guest Editor

1. Department of Medical Research, E-Da Hospital/E-Da Cancer Hospital, Kaohsiung, Taiwan
2. Department of Nursing, College of Medicine, I-Shou University, Kaohsiung, Taiwan
Interests: tumor microenvironment; GRP78; Nrf2; extracellular vesicles; mitochondria; gastric cancer; breast cancer; cancer stemness
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Dr. Cheng-Che Lee

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Guest Editor

School of Medicine for International Student, I-Shou University, Kaohsiung, Taiwan
Interests: MEC-17; EGFR; tumor invasion; autophagy; apoptosis
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Chemotherapy is the treatment of choice for cancer, but the currently available therapeutic drugs for it have limited efficacy. Recent studies have suggested that cancer stem cells in the tumor microenvironment may play an important role in the drug resistance of chemotherapy. The tumor microenvironment, comprising cellular components, such as cancer-associated fibroblasts, tumor-associated macrophages, tumor-associated neutrophils and endothelial cells, has been recognized as a critical contributor to the development and progression of cancer. As the seed and soil hypothesis states that the tumor microenvironment, as a main driver, promotes cancer stemness and therapeutic resistance in most cancers, new agents or treatment strategies that modulate the tumor microenvironment are urgently needed. Regarding this concept, the focus of this Special Issue is investigations on new treatment strategies and molecular mechanisms of tumor microenvironment targeting for cancer therapy. Topics related to cancer stemness or chemoresistance targeting and so on are welcome.

You can read the publications in the first and second volume here:

https://www.mdpi.com/journal/cimb/special_issues/tumor_microenvironmen

https://www.mdpi.com/journal/cimb/special_issues/4TM89R1QO5

Dr. Ming-Wei Lin
Dr. Cheng-Che Lee
Guest Editors

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Keywords

chemotherapy
cancer
tumor
tumor microenvironment
cancer stem cells
cancer therapy
cancer stemness
chemoresistance

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Published Papers (9 papers)

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Research

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13 pages, 3171 KiB

Open AccessArticle

K-Homology Splicing Regulatory Protein (KSRP) Augments Survival and Proliferation of Human Melanoma Cells

by Harunur Rashid, Mohammad Asif Sherwani, Jung Vin Seo, Azeem Ahmad, Sumaiya Tasnim, Quamarul Hassan and Nabiha Yusuf

Curr. Issues Mol. Biol. 2025, 47(5), 356; https://doi.org/10.3390/cimb47050356 - 13 May 2025

Viewed by 136

Abstract

Melanoma is one of the most aggressive and fatal cancers; however, effective and long-lasting treatment options for melanoma continue to be sought after due to the development of resistance mechanisms to the currently available therapies. Background: The K-homology-type splicing regulatory protein (KSRP) is an RNA-binding regulatory protein that binds to the AU-rich elements at the 3′-UTR of target mRNAs. Prior studies have demonstrated that KSRP plays a crucial role in the post-transcriptional regulation of gene expression in human melanoma. Subsequently, in this study, we further examined the role of KSRP in cell migration, colony formation, apoptosis, and tumorigenicity of human melanoma. Methods: KSRP was knocked down in two different human melanoma cell lines: A375 and SK-MEL-28, using lenti-shRNA techniques. By doing so, we studied the effects of KSRP inhibition on cell migration, colony formation, proliferation, apoptosis, and tumorigenicity in these melanoma cell lines. Results: We observed a significant decrease in cell migration, colony formation, proliferation, and tumorigenicity, while also observing a substantial increase in apoptosis in the KSRP knock down melanoma cell lines. Conclusions: Our data establishes that KSRP plays a vital role in cell migration, colony formation, proliferation, apoptosis, and tumorigenicity in both the A375 and SK-MEL-28 human melanoma cell lines. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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11 pages, 1418 KiB

Open AccessArticle

The Role of BCL-2 Expression in Patients with Myelodysplastic Neoplasms

by Bartłomiej Kuszczak, Krzysztof Zduniak, Angela Jendzierowska, Tomasz Wróbel, Piotr Ziółkowski and Justyna Rybka

Curr. Issues Mol. Biol. 2025, 47(5), 346; https://doi.org/10.3390/cimb47050346 - 10 May 2025

Viewed by 129

Abstract

Myelodysplastic neoplasms (MDS) represent a heterogeneous group of neoplastic bone marrow disorders. A crucial component in regulating bone marrow cell apoptosis is the B-cell CLL/lymphoma 2 (BCL-2) protein. This retrospective study aimed to assess BCL-2 expression by immunohistochemistry in trephine biopsy specimens from 76 patients diagnosed with MDS. The obtained retrospective results were correlated with clinical parameters, including age, sex, MDS subtype, IPSS, IPSS-R, bone marrow blast percentage, Ogata score, response to treatment, blood morphology parameters, and overall survival (OS). The median follow-up duration was 16 months. During the observation period, 58 patients died (median OS of this group: 14.6 months), and 25 patients experienced progression to acute myeloid leukemia. The median BCL-2 expression assessed using the Histoscore (H-score) was 10. Patients with BCL-2 expression below 10 had better survival outcomes than those with expression ≥ 10. Furthermore, patients without detectable BCL-2 expression had significantly better survival compared to those with detectable BCL-2 expression (p = 0.0084). Higher BCL-2 expression was significantly associated with high and very high cytogenetic risk, as defined by IPSS-R. BCL-2 immunohistochemistry should be viewed as a complementary biomarker that, when integrated with IPSS-R and mutational data, could refine therapeutic algorithms. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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18 pages, 6069 KiB

Open AccessArticle

Cisplatin-Mediated IL-6 and IDO1 Suppression in Mesenchymal Stromal Cells: Implications for Tumor Microenvironment Modulation In Vitro

by Armin von Fournier, Erik Würflein, Helena Moratin, Manuel Stöth, Totta Ehret Kasemo, Marietta Herrmann, Miguel Goncalves, Rudolf Hagen, Stephan Hackenberg, Thomas Gehrke and Agmal Scherzad

Curr. Issues Mol. Biol. 2025, 47(4), 231; https://doi.org/10.3390/cimb47040231 - 27 Mar 2025

Viewed by 324

Abstract

Mesenchymal stromal cells (MSCs) influence tumor biology and immunology by releasing cytokines, chemokines and growth factors. Currently, cisplatin is an integral part of drug-based tumor therapy, for example, in head and neck squamous cell carcinoma (HNSCC). Cisplatin treatment induces apoptosis as a primary mechanism of action; however, additional immunomodulatory effects of cisplatin are gaining interest. The aim of this study is to evaluate the possible immunomodulatory effects of cisplatin in human MSCs (hMSCs). The MSCs, obtained from human bone marrow, were characterized by analyzing plastic adherence, typical surface features, and ability to differentiate. Toxicity analysis of cisplatin’s effects on primary MSCs, including the determination of a subtoxic concentration, was performed using the MTT assay. Enzyme-linked immunosorbent assays (ELISA) and a quantitative real-time polymerase chain reaction (qRT-PCR) were used to identify potentially immunomodulatory factors. Additionally, a scratch assay was performed to evaluate cell migration. First, subtoxic cisplatin concentrations were determined. A significantly reduced protein expression of indoleamine 2,3-dioxygenase 1 (IDO1) in MSCs under the influence of subtoxic cisplatin concentrations was demonstrated. Similarly, IL-6 protein expression was qualitatively reduced at subtoxic concentrations, although without statistical significance. At the mRNA level, qRT-PCR showed a non-significant, cisplatin concentration-dependent reduction in the expression of both IL-6 and IDO1. The scratch assay showed no statistically significant influence on migration after cisplatin treatment. In MSCs, there is tendency to a decrease in IL-6 and IDO1 at both protein and mRNA level after cisplatin exposure. These effects are congruent with each other and dose-dependent. This indicates that cisplatin not only acts via the known cytotoxic effect, but may induce a reduction in tumor-supporting proteins, like IL-6 and IDO1, by MSCs in the tumor microenvironment at subtoxic concentrations. Traditional cytostatic compounds, which can favorably modulate the immune system in the tumor microenvironment, may open new avenues to explore treatment strategies specifically targeting immunomodulation. Overall, the results indicate beneficial immunomodulation by cisplatin. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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13 pages, 4214 KiB

Open AccessArticle

Correlation of PD-L1 and HIF-1 Alpha Expression with KRAS Mutation and Clinicopathological Parameters in Non-Small Cell Lung Cancer

by Seda Er Özilhan, Safa Can Efil, Doğukan Çanakçı, Yetkin Ağaçkıran, Didem Şener Dede, Nilüfer Onak Kandemir, Mehmet Doğan, Tuba Dilay Kökenek Ünal, Merve Meryem Kıran, Serra Kayaçetin, Hilal Balta and Hayriye Tatlı Doğan

Curr. Issues Mol. Biol. 2025, 47(2), 121; https://doi.org/10.3390/cimb47020121 - 13 Feb 2025

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Abstract

Background: Lung cancer remains the leading cause of cancer-related deaths worldwide, with non-small cell lung carcinomas (NSCLCs) comprising the majority of cases. Among the common driver mutations, KRAS plays a critical role in guiding treatment strategies. This study evaluates the expression of programmed death-ligand 1 (PD-L1) and hypoxia-inducible factor 1-alpha (HIF-1α) in KRAS-mutant NSCLCs and investigates their associations with clinicopathological findings. Methods: A total of 85 cases with KRAS mutations were analyzed. Immunohistochemical staining for HIF-1α and PD-L1 was performed, and their relationships with mutation status and prognostic variables were assessed. Results: A significant correlation was identified between HIF-1α expression and PD-L1 expression in tumor cells. While the KRAS G12C mutation was not significantly associated with HIF-1α expression in tumor cells, it demonstrated a notable relationship with HIF-1α expression in the tumor microenvironment and PD-L1 expression. However, PD-L1 and HIF-1α expression did not significantly influence overall survival outcomes. Conclusions: Expression of PD-L1 was positively correlated with HIF-1α, which may provide evidence for a novel therapy targeting PD-L1 and HIF-1α in NSCLC. Further comprehensive studies are warranted to elucidate the prognostic implications of tumor–microenvironment and mutation interactions. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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13 pages, 727 KiB

Open AccessArticle

The Potential Role of sPD-L1 as a Predictive Biomarker in EGFR-Positive Non-Small-Cell Lung Cancer

by Vesna Ćeriman Krstić, Dragana Jovanović, Natalija Samardžić, Milija Gajić, Jelena Kotur Stevuljević, Aleksandra Klisic, Ivan Soldatović, Damir Radončić, Marina Roksandić Milenković, Biljana Šeha, Nikola Čolić, Katarina Lukić and Milan Savić

Curr. Issues Mol. Biol. 2025, 47(1), 45; https://doi.org/10.3390/cimb47010045 - 11 Jan 2025

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Abstract

Background/Objectives: A significant breakthrough in non-small-cell lung cancer (NSCLC) treatment has occurred with the introduction of targeted therapies and immunotherapy. However, not all patients treated with these therapies would respond to treatment, and patients who respond to treatment would acquire resistance at some time point. This is why we need new biomarkers that can predict response to therapy. The aim of this study was to investigate whether soluble programmed cell death-ligand 1 (sPD-L1) could be a predictive biomarker in patients with epidermal growth factor receptor (EGFR)-positive NSCLC. Materials and Methods: Blood samples from 35 patients with EGFR-mutated (EGFRmut) adenocarcinoma who achieved disease control with EGFR tyrosine kinase inhibitor (EGFR TKI) therapy were collected for sPD-L1 analysis. We analyzed sPD-L1 concentrations in 30 healthy middle-aged subjects, as a control population, to determine the reference range. Adenocarcinoma patients were divided into two groups, i.e., a group with low sPD-L1 (≤182.5 ng/L) and a group with high sPD-L1 (>182.5 ng/L). Results: We found that progression-free survival (PFS) was 18 months, 95% CI (11.1–24.9), for patients with low sPD-L1 and 25 months, 95% CI (8.3–41.7), for patients with high sPD-L1. There was no statistically significant difference in PFS between the groups (p = 0.100). Overall survival (OS) was 34.4 months, 95% CI (26.6–42.2), for patients with low sPD-L1 and 84.1 months, 95% CI (50.6–117.6), for patients with high sPD-L1; there was also no statistically significant difference between the groups (p = 0.114). Conclusion: In our study, we found that patients with high sPD-L1 had numerically better PFS and OS, but this has no statistical significance. Further studies with a larger number of patients are needed to evaluate the role of sPD-L1 as a predictive biomarker in patients with EGFRmut NSCLC. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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13 pages, 40332 KiB

Open AccessArticle

Acidic Microenvironment Enhances Cisplatin Resistance in Bladder Cancer via Bcl-2 and XIAP

by Kaede Hiruma, Vladimir Bilim, Akira Kazama, Yuko Shirono, Masaki Murata and Yoshihiko Tomita

Curr. Issues Mol. Biol. 2025, 47(1), 43; https://doi.org/10.3390/cimb47010043 - 10 Jan 2025

Viewed by 1128

Abstract

Cisplatin (CDDP) remains a key drug for patients with advanced bladder cancer (BC), despite the emergence of new therapeutic agents; thus, the identification of factors contributing to CDDP treatment resistance is crucial. As acidity of the tumor microenvironment has been reported to be associated with treatment resistance and poor prognosis across various cancer types, our objectives in this study were to investigate the effects of an acidic environment on BC cells and elucidate the mechanisms behind CDDP resistance. Our findings show that BC cells cultured under acidic conditions developed cisplatin resistance as acidity increased. Notably, CDDP administered to BC cells in a pH 6.0 environment required double the concentration, compared to those in a pH 7.5 environment, to achieve equivalent toxicity. Using chloroquine and navitoclax, we identified the involvement of the Bcl-2 and LC3B pathways in the acquisition of CDDP resistance under acidic conditions. A Western blot analysis revealed that the activations of Bcl-2 and XIAP expression appear to inhibit both apoptotic and autophagic cell death. Taken together, these results suggest that alleviating the acidity of the tumor microenvironment in clinical settings might enhance BC sensitivity to CDDP. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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Review

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19 pages, 1448 KiB

Open AccessReview

EpCAM Signaling in Oral Cancer Stem Cells: Implications for Metastasis, Tumorigenicity, and Therapeutic Strategies

by Chuan-Hsin Chang, Chung-Che Tsai, Fu-Ming Tsai, Tin-Yi Chu, Po-Chih Hsu and Chan-Yen Kuo

Curr. Issues Mol. Biol. 2025, 47(2), 123; https://doi.org/10.3390/cimb47020123 - 14 Feb 2025

Viewed by 1182

Abstract

Oral cancer, a subtype of head and neck cancer, poses significant global health challenges owing to its late diagnosis and high metastatic potential. The epithelial cell adhesion molecule (EpCAM), a transmembrane glycoprotein, has emerged as a critical player in cancer biology, particularly in oral cancer stem cells (CSCs). This review highlights the multifaceted roles of EPCAM in regulating oral cancer metastasis, tumorigenicity, and resistance to therapy. EpCAM influences key pathways, including Wnt/β-catenin and EGFR, modulating CSC self-renewal, epithelial-to-mesenchymal transition (EMT), and immune evasion. Moreover, EpCAM has been implicated in metabolic reprogramming, epigenetic regulation, and crosstalk with other signaling pathways. Advances in EpCAM-targeting strategies, such as monoclonal antibodies, chimeric antigen receptor (CAR) T/NK cell therapies, and aptamer-based systems hold promise for personalized cancer therapies. However, challenges remain in understanding the precise mechanism of EpCAM in CSC biology and its translation into clinical applications. This review highlights the need for further investigation into the role of EPCAM in oral CSCs and its potential as a therapeutic target to improve patient outcomes. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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28 pages, 3246 KiB

Open AccessReview

Transmembrane Amino Acid Transporters in Shaping the Metabolic Profile of Breast Cancer Cell Lines: The Focus on Molecular Biological Subtype

by Elena I. Dyachenko and Lyudmila V. Bel’skaya

Curr. Issues Mol. Biol. 2025, 47(1), 4; https://doi.org/10.3390/cimb47010004 - 25 Dec 2024

Cited by 1 | Viewed by 1205

Abstract

Amino acid metabolism in breast cancer cells is unique for each molecular biological subtype of breast cancer. In this review, the features of breast cancer cell metabolism are considered in terms of changes in the amino acid composition due to the activity of transmembrane amino acid transporters. In addition to the main signaling pathway PI3K/Akt/mTOR, the activity of the oncogene c-Myc, HIF, p53, GATA2, NF-kB and MAT2A have a direct effect on the amino acid metabolism of cancer cells, their growth and proliferation, as well as the maintenance of homeostatic equilibrium. A distinctive feature of luminal subtypes of breast cancer from TNBC is the ability to perform gluconeogenesis. Breast cancers with a positive expression of the HER2 receptor, in contrast to TNBC and luminal A subtype, have a distinctive active synthesis and consumption of fatty acids. It is interesting to note that amino acid transporters exhibit their activity depending on the pH level inside the cell. In the most aggressive forms of breast cancer or with the gradual progression of the disease, pH will also change, which will directly affect the metabolism of amino acids. Using the cell lines presented in this review, we can trace the characteristic features inherent in each of the molecular biological subtypes of breast cancer and develop the most optimal therapeutic targets. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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32 pages, 910 KiB

Open AccessReview

Interleukin-12 Delivery Strategies and Advances in Tumor Immunotherapy

by Chunyan Dong, Dejiang Tan, Huimin Sun, Zhuang Li, Linyu Zhang, Yiyang Zheng, Sihan Liu, Yu Zhang and Qing He

Curr. Issues Mol. Biol. 2024, 46(10), 11548-11579; https://doi.org/10.3390/cimb46100686 - 16 Oct 2024

Cited by 4 | Viewed by 3925

Abstract

Interleukin-12 (IL-12) is considered to be a promising cytokine for enhancing an antitumor immune response; however, recombinant IL-12 has shown significant toxicity and limited efficacy in early clinical trials. Recently, many strategies for delivering IL-12 to tumor tissues have been developed, such as modifying IL-12, utilizing viral vectors, non-viral vectors, and cellular vectors. Previous studies have found that the fusion of IL-12 with extracellular matrix proteins, collagen, and immune factors is a way to enhance its therapeutic potential. In addition, studies have demonstrated that viral vectors are a good platform, and a variety of viruses such as oncolytic viruses, adenoviruses, and poxviruses have been used to deliver IL-12—with testing previously conducted in various cancer models. The local expression of IL-12 in tumors based on viral delivery avoids systemic toxicity while inducing effective antitumor immunity and acting synergistically with other therapies without compromising safety. In addition, lipid nanoparticles are currently considered to be the most mature drug delivery system. Moreover, cells are also considered to be drug carriers because they can effectively deliver therapeutic substances to tumors. In this article, we will systematically discuss the anti-tumor effects of IL-12 on its own or in combination with other therapies based on different delivery strategies. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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