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Immunomodulatory Molecules in Cancer
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Immunomodulatory Molecules in Cancer

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

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 15641

Special Issue Editor

Dr. Georgios Pantouris

E-Mail Website
Guest Editor
Department of Chemistry, University of the Pacific, Stockton, CA 95211, USA
Interests: structural biology; drug discovery; cancer biology; protein dynamics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the modern era of cancer treatment, targeted therapeutic approaches not only extend the lifespan of cancer patients but also improve their quality of life. In some types of cancer, targeted therapies have shifted the standard of care treatment plans, whereas in others they are employed as a second-, third-, or later-stage setting when the primary treatment plan fails. The success of targeted therapies is associated with the comprehensive and thorough analysis of the tumor microenvironment and the identification of novel immunomodulatory proteins. The upregulation or structural modification of such proteins has been shown to manipulate the immune system, promoting cancer cell survival and metastasis. Therefore, an in-depth understanding of such molecules would lead to the discovery of a new generation of therapeutics that could further support existing personalized treatment plans and provide additional treatment options for advanced metastatic cancers.

This Special Issue entitled, “Immunomodulatory Molecules in Cancer”, is open to original research and review articles from biochemistry, molecular and cell biology, molecular biophysics, molecular medicine, and all aspects of molecular research in chemistry. We welcome studies that provide insights into oncogenic proteins and protein complexes, including fusion proteins. Examples of molecules that fall within the scope of this Special Issue include CD receptors (e.g., CD40, CD47, CD74, and CD137), cytokines (e.g., MIF, D-DT, IFN-γ, TNF-α, and ILs), chemokines  (e.g., CXCLs and CCLs), chemokine receptors (e.g., CXCRs and CCRs), oncogenic enzymes (e.g., IDO, TDO, NQO1, and IDH1), checkpoint proteins (e.g.,  PD1/PDL1), transcription factors (e.g., STAT3), kinases (e.g., ROS1 and NTRK1), the epidermal growth factor (EGFR) family of proteins (e.g., HER1-4), bromodomain-containing proteins, and many more.  Studies that utilize checkpoint inhibitors or other small-molecule probes are also very welcome.

Dr. Georgios Pantouris
Guest Editor

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 short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • cancer
  • immunomodulatory molecules
  • mechanism of action
  • immune system
  • small-molecule probes
  • activation/inhibition
  • biological activity

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Related Special Issue

Published Papers (7 papers)

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Research

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14 pages, 2285 KiB  
Article
Transglutaminase 2 Stimulates Cell Proliferation and Modulates Transforming Growth Factor-Beta Signaling Pathway Independently of Epithelial–Mesenchymal Transition in Hepatocellular Carcinoma Cells
by Hiromi Yamaguchi, Ramiro José González-Duarte, Xian-Yang Qin, Yuriko Abe, Ichiro Takada, Benjamin Charroy, Verna Cázares-Ordoñez, Shigeyuki Uno, Makoto Makishima and Mariko Esumi
Int. J. Mol. Sci. 2025, 26(12), 5497; https://doi.org/10.3390/ijms26125497 - 8 Jun 2025
Viewed by 379
Abstract
Transglutaminase 2 (TG2) is a multifunctional protein and plays a role in cancer progression. We previously identified TG2 as an early-recurrence biomarker in hepatocellular carcinoma (HCC). TG2-knockdown (shTG2) and control (shCtl) HCC cell lines were used for comparative analyses to clarify the molecular [...] Read more.
Transglutaminase 2 (TG2) is a multifunctional protein and plays a role in cancer progression. We previously identified TG2 as an early-recurrence biomarker in hepatocellular carcinoma (HCC). TG2-knockdown (shTG2) and control (shCtl) HCC cell lines were used for comparative analyses to clarify the molecular mechanisms underlying the contribution of this protein to HCC malignancy. The proliferation of shTG2 cells was slightly but significantly decreased compared with that of shCtl cells. Differential gene expression profiling based on GeneChip arrays revealed the enrichment of the PI3K-Akt signaling pathway and showed that the expression of Dickkopf-1 and -3 (DKK1 and DKK3, respectively), inhibitors and modulators of the Wnt/β-catenin signaling pathway, was increased in shTG2 cells. The expression of epithelial–mesenchymal transition (EMT)-related genes was similar in both shCtl and shTG2 cells before and after TGF-β1 treatment, even though TGF-β1 markedly upregulated TG2. Thus, TG2 may contribute to cancer malignancy via the stimulation of cell proliferation signaling, such as PI3K-Akt and Wnt/β-catenin signaling, but not EMT. This effect might be further enhanced by humoral factors such as TGF-β1 from the tumor microenvironment. Full article
(This article belongs to the Special Issue Immunomodulatory Molecules in Cancer)
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16 pages, 2991 KiB  
Article
Anti-Tumor Activities of Anti-Siglec-15 Chimeric Heavy-Chain Antibodies
by Kexuan Cheng, Jiazheng Guo, Yating Li, Qinglin Kang, Rong Wang, Longlong Luo, Wei Wang and Jiansheng Lu
Int. J. Mol. Sci. 2025, 26(11), 5068; https://doi.org/10.3390/ijms26115068 - 24 May 2025
Viewed by 411
Abstract
Immune checkpoint inhibitors like programmed cell death 1 (PD-1) antibodies have revolutionized cancer treatment, but patient response rates remain limited. Sialic acid-binding Ig-like lectin 15 (Siglec-15) has emerged as a promising new immune checkpoint target. Through phage display technology using a Bactrian camel [...] Read more.
Immune checkpoint inhibitors like programmed cell death 1 (PD-1) antibodies have revolutionized cancer treatment, but patient response rates remain limited. Sialic acid-binding Ig-like lectin 15 (Siglec-15) has emerged as a promising new immune checkpoint target. Through phage display technology using a Bactrian camel immunized with recombinant human Siglec-15, we generated six anti-Siglec-15 camelid nanobodies and constructed chimeric heavy-chain antibodies by fusing the VHH domains with human IgG-Fc. Following expression in HEK293-F cells and purification, three antibodies (S1, S5, S6) demonstrated specific binding to both human and murine Siglec-15 in ELISA and biolayer interferometry assays. In a xenograft model established by subcutaneous inoculation of NCI-H157-S15 cells into BALB/c nude mice, these antibodies showed distinct tumor targeting and significant blockade of Siglec-15 interactions with CD44, MAG, sialyl-Tn, and LRR4C ligands. All three antibodies exhibited anti-tumor effects, with S1 showing the most potent activity. S1-treated mice had significantly smaller tumor volumes and weights compared to controls. The S1, S5, and S6 treatment groups showed enhanced anti-tumor immunity, with reduced TGF-β, IL-6, and IL-10 levels. Notably, S1 treatment significantly increased tumor-associated macrophages in tumor tissues (p < 0.05). In conclusion, S1 exhibits remarkable anti-tumor activity and has the potential to be developed as a cancer immunotherapy targeting Siglec-15. Full article
(This article belongs to the Special Issue Immunomodulatory Molecules in Cancer)
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19 pages, 2814 KiB  
Article
Optimizing rWTC-MBTA Vaccine Formulations, Dosing Regimens, and Cryopreservation Techniques to Enhance Anti-Metastatic Immunotherapy
by Juan Ye, Herui Wang, Samik Chakraborty, Xueyu Sang, Qingfeng Xue, Mitchell Sun, Yaping Zhang, Ondrej Uher, Karel Pacak and Zhengping Zhuang
Int. J. Mol. Sci. 2025, 26(3), 1340; https://doi.org/10.3390/ijms26031340 - 5 Feb 2025
Viewed by 975
Abstract
Metastatic cancer poses significant clinical challenges, necessitating effective immunotherapies with minimal systemic toxicity. Building on prior research demonstrating the rWTC-MBTA vaccine’s ability to inhibit tumor metastasis and growth, this study focuses on its clinical translation by optimizing vaccine composition, dosing regimens, and freezing [...] Read more.
Metastatic cancer poses significant clinical challenges, necessitating effective immunotherapies with minimal systemic toxicity. Building on prior research demonstrating the rWTC-MBTA vaccine’s ability to inhibit tumor metastasis and growth, this study focuses on its clinical translation by optimizing vaccine composition, dosing regimens, and freezing techniques. The vaccine formula components included three TLR ligands (LTA, Poly I:C, and Resiquimod) and an anti-CD40 antibody, which were tested in melanoma and triple-negative breast cancer (TNBC) models. The formulations were categorized as rWTC-MBT (Mannan-BAM with LTA, Poly I:C, Resiquimod), rWTC-MBL (LTA), rWTC-MBP (Mannan-BAM with Poly I:C), and rWTC-MBR (Resiquimod). In the melanoma models, all the formulations exhibited efficacy that was comparable to that of the full vaccine, while in the “colder” TNBC models, the formulations with multiple TLR ligands or Resiquimod alone performed the best. Vaccine-induced activation of dendritic cell (DC) subsets, including conventional DCs (cDCs), myeloid DCs (mDCs), and plasmacytoid DCs (pDCs), was accompanied by significant CD80+CD86+ population induction, suggesting robust innate immune stimulation. An initial three-dose schedule followed by booster doses (3-1-1-1 or 3-3-3-3) reduced the metastatic burden effectively. Gradual freezing (DMSO-based preservation) maintained vaccine efficacy, underscoring the importance of intact cell structure. These findings highlight the potential of simplified formulations, optimized dosing, and freezing techniques in developing practical, scalable immunotherapies for metastatic cancers. Full article
(This article belongs to the Special Issue Immunomodulatory Molecules in Cancer)
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Review

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30 pages, 712 KiB  
Review
IL-18 and IL-18BP: A Unique Dyad in Health and Disease
by Daniela Novick
Int. J. Mol. Sci. 2024, 25(24), 13505; https://doi.org/10.3390/ijms252413505 - 17 Dec 2024
Cited by 5 | Viewed by 3429
Abstract
Interleukin-18 (IL-18) serves a dual function in the immune system, acting as a “double-edged sword” cytokine. Depending on the microenvironment and timing, IL-18 can either drive harmful inflammation or restore immune homeostasis. Pathologies characterized by elevated IL-18, recently proposed to be termed IL-18opathies, [...] Read more.
Interleukin-18 (IL-18) serves a dual function in the immune system, acting as a “double-edged sword” cytokine. Depending on the microenvironment and timing, IL-18 can either drive harmful inflammation or restore immune homeostasis. Pathologies characterized by elevated IL-18, recently proposed to be termed IL-18opathies, highlight the therapeutic potential for IL-18 blockade. IL-18 Binding Protein (IL-18BP) is one of only four natural cytokine antagonists encoded by a separate gene, distinguishing it from canonical soluble receptors. IL-18BP’s exceptionally high affinity and slow dissociation rate make it an effective regulator of IL-18, essential for maintaining immune balance and influencing disease outcomes, and positions IL-18BP as a promising alternative to more aggressive treatments that carry risks of severe infections and other complications. Tadekinig alfa, the drug form of IL-18BP, represents a targeted therapy that modulates the IL-18/IL-18BP axis, offering a safe adverse-effect-free option. With orphan drug designation, Phase III clinical trial completion, and seven years of compassionate use, Tadekinig alfa holds promise in treating autoimmune and inflammatory diseases, cancer, and genetically linked disorders. Levels of IL-18, free IL-18 and IL-18BP, may serve as biomarkers for disease severity and therapeutic response. Given its pivotal role in immune balance, the IL-18/IL-18BP dyad has attracted interest from over ten pharmaceutical companies and startups, which are currently developing innovative strategies to either inhibit or enhance IL-18 activity depending on the therapeutic need. The review focuses on the features of the dyad members and screens the therapeutic approaches. Full article
(This article belongs to the Special Issue Immunomodulatory Molecules in Cancer)
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22 pages, 937 KiB  
Review
Inflammasomes Are Influenced by Epigenetic and Autophagy Mechanisms in Colorectal Cancer Signaling
by Györgyi Műzes and Ferenc Sipos
Int. J. Mol. Sci. 2024, 25(11), 6167; https://doi.org/10.3390/ijms25116167 - 3 Jun 2024
Cited by 3 | Viewed by 1372
Abstract
Inflammasomes contribute to colorectal cancer signaling by primarily inducing inflammation in the surrounding tumor microenvironment. Its role in inflammation is receiving increasing attention, as inflammation has a protumor effect in addition to inducing tissue damage. The inflammasome’s function is complex and controlled by [...] Read more.
Inflammasomes contribute to colorectal cancer signaling by primarily inducing inflammation in the surrounding tumor microenvironment. Its role in inflammation is receiving increasing attention, as inflammation has a protumor effect in addition to inducing tissue damage. The inflammasome’s function is complex and controlled by several layers of regulation. Epigenetic processes impact the functioning or manifestation of genes that are involved in the control of inflammasomes or the subsequent signaling cascades. Researchers have intensively studied the significance of epigenetic mechanisms in regulation, as they encompass several potential therapeutic targets. The regulatory interactions between the inflammasome and autophagy are intricate, exhibiting both advantageous and harmful consequences. The regulatory aspects between the two entities also encompass several therapeutic targets. The relationship between the activation of the inflammasome, autophagy, and epigenetic alterations in CRC is complex and involves several interrelated pathways. This article provides a brief summary of the newest studies on how epigenetics and autophagy control the inflammasome, with a special focus on their role in colorectal cancer. Based on the latest findings, we also provide an overview of the latest therapeutic ideas for this complex network. Full article
(This article belongs to the Special Issue Immunomodulatory Molecules in Cancer)
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18 pages, 881 KiB  
Review
Roles of Interferon Regulatory Factor 1 in Tumor Progression and Regression: Two Sides of a Coin
by Alina M. Perevalova, Lyudmila F. Gulyaeva and Vladimir O. Pustylnyak
Int. J. Mol. Sci. 2024, 25(4), 2153; https://doi.org/10.3390/ijms25042153 - 10 Feb 2024
Cited by 9 | Viewed by 3205
Abstract
IRF1 is a transcription factor well known for its role in IFN signaling. Although IRF1 was initially identified for its involvement in inflammatory processes, there is now evidence that it provides a function in carcinogenesis as well. IRF1 has been shown to affect [...] Read more.
IRF1 is a transcription factor well known for its role in IFN signaling. Although IRF1 was initially identified for its involvement in inflammatory processes, there is now evidence that it provides a function in carcinogenesis as well. IRF1 has been shown to affect several important antitumor mechanisms, such as induction of apoptosis, cell cycle arrest, remodeling of tumor immune microenvironment, suppression of telomerase activity, suppression of angiogenesis and others. Nevertheless, the opposite effects of IRF1 on tumor growth have also been demonstrated. In particular, the “immune checkpoint” molecule PD-L1, which is responsible for tumor immune evasion, has IRF1 as a major transcriptional regulator. These and several other properties of IRF1, including its proposed association with response and resistance to immunotherapy and several chemotherapeutic drugs, make it a promising object for further research. Numerous mechanisms of IRF1 regulation in cancer have been identified, including genetic, epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms, although their significance for tumor progression remains to be explored. This review will focus on the established tumor-suppressive and tumor-promoting functions of IRF1, as well as the molecular mechanisms of IRF1 regulation identified in various cancers. Full article
(This article belongs to the Special Issue Immunomodulatory Molecules in Cancer)
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19 pages, 1379 KiB  
Review
Analysis of CD74 Occurrence in Oncogenic Fusion Proteins
by Jasmine Vargas and Georgios Pantouris
Int. J. Mol. Sci. 2023, 24(21), 15981; https://doi.org/10.3390/ijms242115981 - 5 Nov 2023
Cited by 3 | Viewed by 3988
Abstract
CD74 is a type II cell surface receptor found to be highly expressed in several hematological and solid cancers, due to its ability to activate pathways associated with tumor cell survival and proliferation. Over the past 16 years, CD74 has emerged as a [...] Read more.
CD74 is a type II cell surface receptor found to be highly expressed in several hematological and solid cancers, due to its ability to activate pathways associated with tumor cell survival and proliferation. Over the past 16 years, CD74 has emerged as a commonly detected fusion partner in multiple oncogenic fusion proteins. Studies have found CD74 fusion proteins in a range of cancers, including lung adenocarcinoma, inflammatory breast cancer, and pediatric acute lymphoblastic leukemia. To date, there are five known CD74 fusion proteins, CD74-ROS1, CD74-NTRK1, CD74-NRG1, CD74-NRG2α, and CD74-PDGFRB, with a total of 16 different variants, each with unique genetic signatures. Importantly, the occurrence of CD74 in the formation of fusion proteins has not been well explored despite the fact that ROS1 and NRG1 families utilize CD74 as the primary partner for the formation of oncogenic fusions. Fusion proteins known to be oncogenic drivers, including those of CD74, are typically detected and targeted after standard chemotherapeutic plans fail and the disease relapses. The analysis reported herein provides insights into the early intervention of CD74 fusions and highlights the need for improved routine assessment methods so that targeted therapies can be applied while they are most effective. Full article
(This article belongs to the Special Issue Immunomodulatory Molecules in Cancer)
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