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Cancers
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NK Cells in the Tumor Microenvironment: Immunosuppressive Mechanisms and Therapy
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NK Cells in the Tumor Microenvironment: Immunosuppressive Mechanisms and Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: 5 December 2025 | Viewed by 1695

Special Issue Editors

Dr. Alexander Barrow

E-Mail Website
Guest Editor
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia
Interests: immunology; viral infectious diseases; cancer immunology
Special Issues, Collections and Topics in MDPI journals
Dr. Julian Vivian

E-Mail Website
Guest Editor
1. St. Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
2. Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
Interests: protein chemistry; protein imaging; T cells; natural killer cells; cancer

Special Issue Information

Dear Colleagues,

Natural killer (NK) cells represent the innate counterparts of cytotoxic T lymphocytes, poised to rapidly engage in cell-mediated cytotoxicity and the release of potent proinflammatory cytokines. Their functions are largely regulated through surface-activating and inhibitory receptors which probe their tissue microenvironment for signs of infection or malignancy. Therapeutic manipulation of these opposing receptors holds great promise for clinical intervention. In this Special Issue, we explore the mechanisms malignant cells employ to inhibit NK cell surveillance, as well as therapeutic strategies to overcome these immunosuppressive pathways and enhance NK cell activity.

Dr. Alexander Barrow
Dr. Julian Vivian
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 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. 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

  • immunosuppression
  • activation
  • inhibition
  • receptor
  • NK-CAR
  • checkpoint
  • adoptive cell therapy
  • immunotherapy
  • tumor microenvironment
  • nanoparticles

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Published Papers (2 papers)

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Research

20 pages, 7995 KiB  
Article
Reduced HLA-I Transcript Levels and Increased Abundance of a CD56dim NK Cell Signature Are Associated with Improved Survival in Lower-Grade Gliomas
by Md Abdullah Al Kamran Khan, Lorenza Peel, Alexander J. Sedgwick, Yuhan Sun, Julian P. Vivian, Alexandra J. Corbett, Riccardo Dolcetti, Theo Mantamadiotis and Alexander D. Barrow
Cancers 2025, 17(9), 1570; https://doi.org/10.3390/cancers17091570 - 5 May 2025
Viewed by 405
Abstract
Background: Human leukocyte antigen class I (HLA-I) plays a pivotal role in shaping anti-tumour immunity by influencing the functionality of T cells and natural killer (NK) cells within the tumour microenvironment. Methods: Here, we explored the transcriptional landscape of HLA-I molecules across various [...] Read more.
Background: Human leukocyte antigen class I (HLA-I) plays a pivotal role in shaping anti-tumour immunity by influencing the functionality of T cells and natural killer (NK) cells within the tumour microenvironment. Methods: Here, we explored the transcriptional landscape of HLA-I molecules across various solid cancer transcriptomes from The Cancer Genome Atlas (TCGA) database and assessed the impact of HLA-I expression on the clinical significance of tumour-infiltrating CD56dim and CD56bright NK cells. Results: Our analysis revealed that high HLA-I expression correlated with reduced patient survival in the TCGA lower-grade glioma (LGG) cohort, with this association varying by histopathological subtype. We then estimated the relative abundance of 23 immune and stromal cell signatures in LGG transcriptomes using a cellular deconvolution approach, which revealed that LGG patients with low HLA-I expression and high CD56dim NK cell abundance had better survival outcomes compared to those with high HLA-I expression and low CD56dim NK cell abundance. Furthermore, HLA-I expression was positively correlated with various inhibitory NK cell receptors and negatively correlated with activating NK cell receptors, particularly those within the killer cell lectin-like receptor (KLR) gene family. High co-expression of HLA-E and NKG2A predicted poor survival outcomes in LGG patients, whereas low HLA-E and high NKG2C/E abundance predicted more favourable outcomes, suggesting a potential modulatory role of HLA-I on the tumour-infiltrating cytotoxic CD56dim NK cell subset. Conclusions: Overall, our study unveils a potential role for deregulated HLA-I expression in modulating the clinical impact of glioma-infiltrating CD56dim NK cells. These findings lay the foundation for future in-depth experimental studies to investigate the underlying mechanisms. Full article
(This article belongs to the Special Issue NK Cells in the Tumor Microenvironment: Immunosuppressive Mechanisms and Therapy)
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22 pages, 5842 KiB  
Article
Axl Regulation of NK Cell Activity Creates an Immunosuppressive Tumor Immune Microenvironment in Head and Neck Cancer
by Kourtney L. Kostecki, Regan L. Harmon, Mari Iida, Madelyn A. Harris, Bridget E. Crossman, Justine Yang Bruce, Ravi Salgia and Deric L. Wheeler
Cancers 2025, 17(6), 994; https://doi.org/10.3390/cancers17060994 - 15 Mar 2025
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Abstract
Background: Head and neck cancer (HNC) evades immune responses by manipulating the tumor immune microenvironment (TIME). Tumor-bound Axl has been implicated in promoting an immunosuppressive TIME in HNC, though its precise role remains unclear. Understanding Axl’s contribution to immune evasion in HNC [...] Read more.
Background: Head and neck cancer (HNC) evades immune responses by manipulating the tumor immune microenvironment (TIME). Tumor-bound Axl has been implicated in promoting an immunosuppressive TIME in HNC, though its precise role remains unclear. Understanding Axl’s contribution to immune evasion in HNC could lead to the identification of new therapeutic targets; therapies directed at these targets could be combined with and thereby enhance immunotherapies. Results: Using Axl knockout (Axl KO) cell lines derived from the immunologically “cold” MOC2 mouse model, we found that Axl loss delayed tumor growth in immunocompetent mice. This was accompanied by reduced immunosuppressive cells, including MDSCs, Tregs, B cells, and neutrophils, and increased infiltration of cytotoxic CD8 T cells and NK cells. To identify the immune population(s) responsible for these changes, Axl KO tumors were implanted in immune-deficient mice. Axl KO tumor growth in athymic nude mice (which lack T cells) was unchanged, whereas tumor growth in NCG mice (which lack NK cells) was rescued, suggesting that NK cells mediate the Axl KO tumor growth delay. Further, Axl loss enhanced NK cell cytotoxicity in vitro and in vivo, and NK cell depletion reversed delayed Axl KO tumor growth. Mechanistically, Axl KO tumors showed decreased expression of CD73 and CCL2, which inhibit NK cells, and increased expression of CCL5 and CXCL10, which promote NK cell recruitment and activation. Conclusions: These novel findings suggest that tumor-bound Axl fosters an immunosuppressive TIME by inhibiting NK cell recruitment and function, thereby promoting tumor growth. Targeting Axl may enhance NK cell-mediated tumor killing and improve immunotherapy efficacy in HNC. Full article
(This article belongs to the Special Issue NK Cells in the Tumor Microenvironment: Immunosuppressive Mechanisms and Therapy)
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