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Advances in Cellular Heterogeneity and Plasticity in the Tumor Microenvironment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: 15 April 2026 | Viewed by 909

Special Issue Editors


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Guest Editor
1. Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
2. Department of Biomedical Sciences, “Our Lady of Good Counsel” University, Rruga Dritan Hoxha, 1000 Tirana, Albania
Interests: molecular mechanisms associated with tumor growth and progression linked to angiogenesis; molecular mechanisms associated with polarized immune cells in the tumor microenvironment; effects of angiogenic factors on vascular biology and immune response
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Special Issue Information

Dear Colleagues,

The tumor microenvironment (TME) is an intricate and heterogeneous environment consisting of tumor cells and various cell types, including endothelial cells, immune cells, fibroblasts, and extracellular matrix components, in which each element can influence the others. Although the TME varies in terms of distinct types of solid tumors, hypoxia, nutrient availability, and the release of growth factors and cytokines are the main factors responsible for this heterogeneity. Growth factors and cytokines, by influencing stromal cells’ behavior and attracting immune cells, can induce tumor cells to adopt different phenotypes and increase their structural and functional plasticity through epigenetic changes. Cellular plasticity is now considered to be a hallmark of cancer. It is an intrinsic property of cancer cells characterized by genomic instability, altered signaling, and metabolic reprogramming that allows cancer cells to adapt to the heterogeneity of the microenvironment. Cellular plasticity can also promote the survival of tumor cells under conditions of nutrient restriction and hypoxia. In addition, it is not only involved in epithelial–mesenchymal transition and thus tumor progression but also promotes the evasion of the immune response by rendering tumor cells invisible to the immune system. The result is the development of stem-cell-like cells characterized by low immunogenicity, a high propensity to metastasize, and a high resistance to therapy. Therefore, there is an urgent need to understand the complex interplay between the heterogeneous TME, tumor cell plasticity, tumor immune evasion, and resistance to therapy. This Special Issue aims to collate recent insights into the molecular and cellular mechanisms caused by epigenetic modifications and/or mutational events responsible for tumor cell plasticity, with the aim of identifying new possible therapeutic targets.

Scope and information for Authors:

For this Special Issue, we welcome the submission of reviews, mini-reviews, and original research articles that offer new insights into the following subtopics:

  • Crosstalk between cancer cells and non-tumoral stromal and immune cells in the TME;
  • Molecular mechanisms driving tumor cell plasticity;
  • Reciprocal interplay between tumor cell plasticity and infiltrate immune cell types in the TME;
  • Prediction and optimization cellular responses to therapeutic strategies that target tumor cell plasticity in the TME.

Dr. Loredana Albonici
Dr. Manuel Scimeca
Guest Editors

Manuscript Submission Information

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 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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor microenvironment (TME)
  • tumor microenvironmental heterogeneity and drug resistance
  • cancer cell plasticity and immune evasion
  • epithelial–mesenchymal transition (EMT)
  • tumor immune context

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Published Papers (1 paper)

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Research

19 pages, 7649 KB  
Article
Comparative Oncology: Cross-Sectional Single-Cell Transcriptomic Profiling of the Tumor Microenvironment Across Seven Human Cancers
by Riku Okamoto, Kota Okuno, Akiko Watanabe, Kanako Naito, Hiroyuki Minoura, Shumpei Shibaki, Kyonosuke Ikemura, Keiko Oki, Yu Kuroda, Shiori Fujino, Yusuke Nie, Nobuyuki Nishizawa, Eiichiro Watanabe, Mariko Kikuchi, Koshi Kumagai, Takahiro Yamanashi, Hiroshi Katoh, Hajime Takayasu, Takeo Sato, Takafumi Sangai, Yusuke Kumamoto, Takeshi Naitoh, Naoki Hiki and Keishi Yamashitaadd Show full author list remove Hide full author list
Cancers 2025, 17(21), 3527; https://doi.org/10.3390/cancers17213527 - 31 Oct 2025
Viewed by 698
Abstract
Background/Objectives: To elucidate the differential transcriptional and intercellular signaling features of tumor components across various cancers, we conducted a comparative analysis using single-cell RNA sequencing (scRNA-seq). This technology enables detailed characterization of tumor ecosystems and may explain variations in tumor behavior among [...] Read more.
Background/Objectives: To elucidate the differential transcriptional and intercellular signaling features of tumor components across various cancers, we conducted a comparative analysis using single-cell RNA sequencing (scRNA-seq). This technology enables detailed characterization of tumor ecosystems and may explain variations in tumor behavior among distinct cancer types. Methods: We analyzed publicly available scRNA-seq datasets (GEO) from seven cancer types—pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), esophageal squamous cell carcinoma (ESCC), breast cancer (BC), thyroid cancer (TC), gastric cancer (GC), and colorectal cancer (CRC)—to define their unique molecular characteristics and intercellular interactions. Results: PDAC displayed a distinct tumor microenvironment (TME) dominated by myeloid cells (~42%), including abundant CXCR1/CXCR2-expressing tumor-associated neutrophils (TANs) that preferentially interacted with immune rather than cancer cells. The competitive receptor ACKR1 was minimally expressed on endothelial cells, consistent with PDAC hypo-vascularity. In HCC, tumor cells lacked EPCAM and expressed complement and stem cell markers; cancer-associated fibroblasts (CAFs) were scarce, and stellate cells expressed the pericyte marker RGS5. CAFs were abundant in ESCC and BC, with IGF1/2 expression, while in GC, these markers were uniquely found in plasma cells. Since BC and GC subtypes exhibit distinct TME patterns, it is necessary to perform subtype-specific analyses for these cancers. TC showed high expression of tumor-suppressor genes, including HOPX, in tumor cells. Differential interactions and the presence of “dominant signaling cell populations “ with dominant outgoing signals may underlie the heterogeneity in tumor aggressiveness across these cancers. Conclusions: Comparative scRNA-seq analysis of multiple cancers reveals distinct tumor phenotypes and cell–cell communication patterns, offering insights into the molecular architecture of human solid tumors. Full article
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