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Novel Immunotherapies for Reshaping the Tumor Immune Microenvironment

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 October 2026 | Viewed by 1312

Special Issue Editor


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Guest Editor
Division of Gynecologic Oncology, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
Interests: cell biology; tumor biology; cancer immunotherapy; TME; tumor infiltrating myeloid and T cells; tumor immune escape; immunotherapy; drug resistance
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Special Issue Information

Dear Colleagues,

Cancer immune infiltration plays a crucial role in cancer progression and response to immunotherapies. The tumor immune microenvironment (TIME), composed of immune cells, stromal elements, and signaling molecules, can either support anti-tumor immunity or promote immune evasion. Recent studies highlight the need to understand how tumors manipulate immune responses to enhance progression, drug resistance, and survival. In immunosuppressive tumors, increased infiltration of activated regulatory T cells, myeloid-derived suppressive cells (MDSCs), and the immunosuppressive reprogramming of neutrophils and macrophages contribute to angiogenesis, tumor growth, metastasis, alter inflammation and immune checkpoint expression. These changes impair cytotoxic immune cell trafficking and activation. However, the immune reprogramming of the TME has not been fully uncovered. A deeper understanding of the biological mechanisms shaping the TIME during tumor progression is essential for developing more effective immunotherapies, improving patient outcomes, and overcoming drug resistance.

This Special Issue Novel Immunotherapies for Reshaping the Tumor Immune Microenvironment, invites original research and review articles. Topics include but are not limited to:

  • Mechanisms of immune cell reprogramming in the TME
  • Cancer immune evasion strategies
  • Mechanisms of cancer resistance to immunotherapies
  • Development of novel cancer immunotherapies.

Dr. Alessandro Canella
Guest Editor

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Keywords

  • TIME
  • TME
  • immunosuppression
  • inflammation
  • immune cells
  • immunotherapy
  • cancer immune evasion

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Published Papers (1 paper)

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Review

24 pages, 4841 KB  
Review
The Dickkopf-1 (DKK1) Dichotomy in Oncology: New Insights on Tumor Progression and Immune Regulation
by Alessandro Canella, Zachary Gentry and Casey Cosgrove
Int. J. Mol. Sci. 2026, 27(9), 3780; https://doi.org/10.3390/ijms27093780 - 23 Apr 2026
Viewed by 884
Abstract
Dickkopf-1 (DKK1) is a 266-amino-acid secreted glycoprotein originally identified as a high-affinity antagonist of the canonical Wnt/β-catenin signaling pathway and has emerged as a complex regulator in oncology. While historically considered as a tumor suppressor due to its ability to abrogate Wnt-driven proliferation, [...] Read more.
Dickkopf-1 (DKK1) is a 266-amino-acid secreted glycoprotein originally identified as a high-affinity antagonist of the canonical Wnt/β-catenin signaling pathway and has emerged as a complex regulator in oncology. While historically considered as a tumor suppressor due to its ability to abrogate Wnt-driven proliferation, recent discoveries highlight a paradoxical pro-oncogenic role across various malignancies. The molecular mechanisms by which DKK1 promotes tumor progression, metastasis, and immune evasion are driven by its interaction with cell-surface receptors, specifically LRP5/6 and CKAP4. The DKK1-CKAP4 axis independently activates PI3K/AKT signaling, facilitating epithelial–mesenchymal transition (EMT), chemoresistance, and the formation of osteolytic bone lesions. Furthermore, DKK1 serves as a critical orchestrator of the tumor microenvironment (TME) by driving comprehensive immune reprogramming. It mediates the recruitment of myeloid-derived suppressor cells (MDSCs) and inactivates cytotoxic CD8+ T cells and natural killer (NK) cells, thereby fostering an immunosuppressive tumor microenvironment and resistance to checkpoint inhibitors. Interestingly, cancer-associated fibroblasts (CAFs) are a primary source of DKK1 in the stroma, where they facilitate immune evasion. Clinically, elevated circulating DKK1 levels correlate with advanced disease stages, increased metastatic potential, and poor overall survival in solid and hematological tumors. When used in combination with established biomarkers, serum DKK1 levels demonstrate significant utility for early detection and therapeutic monitoring. Given its intricate impact on malignancy, DKK1 has become a promising therapeutic target, with ongoing clinical trials investigating neutralizing antibodies such as DKN-01 to disrupt its oncogenic and immunosuppressive signaling. Understanding the context-dependent nature of DKK1 signaling remains essential for refining its application as both a biomarker and a component of emerging precision immunotherapy strategies. By prioritizing the literature from the last decade, this review characterizes DKK1 as a key mediator of tumor progression and immune reprogramming, while assessing its clinical potential as a biomarker and therapeutic target. Full article
(This article belongs to the Special Issue Novel Immunotherapies for Reshaping the Tumor Immune Microenvironment)
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