Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Feeling exhausted, no longer – macrophages keep type 2 innate lymphoid cells energized

Cellular & Molecular Immunology volume 22, pages 1645–1647 (2025)Cite this article

Subjects

The Original Article was published on 24 September 2025

Tissue-resident type 2 innate lymphoid cells (ILC2s) help orchestrate local inflammation. As early responding cells to danger signals and tissue damage, they produce key cytokines that directly influence the breadth and depth of the immune response, including surveillance during tumor development and progression. Like T cells, ILC2s express immune checkpoint molecules on their surface that regulate their effector function. In lung cancer, Ciancaglini et al. [1] discovered that ILC2s from malignant pleural effusions express cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which, through direct binding to CD80/CD86+ macrophages, limits their effector function. In the tumor microenvironment, this interaction with macrophages puts ILC2s in a reversible hypo-responsive state, preventing ILC2 exhaustion and allowing them to be subsequently activated when stimulated with alarmins. These findings shed new light on the regulation of ILC2s and how interactions of ILC2s with other immune cells in the cancer microenvironment regulate their activity, with potential implications for antitumor immunity and immunotherapy efficacy.

Cancer prognosis and disease outcomes are dictated by the quality of the immune response, which is often simplistically dichotomized into either a type 1 or type 2 immune response. Type 1 immune responses, characterized by high tumor infiltration of IFN-γ+ cytotoxic immune cells, are often associated with improved survival and response to treatments, whereas high infiltration of Th2 cells and ILC2s, as prototypical drivers of type 2 immunity, is often correlated with disease progression and poor outcomes [2, 3]. Although high ILC2 infiltration in melanoma and pancreatic tumors is correlated with better tumor control and improved survival, the presence of ILC2s in promyelocytic leukemia and bladder, prostate, and breast cancer has been associated with poor disease outcomes [4, 5]. These seemingly paradoxical outcomes highlight the pleiotropic role ILC2s play in cancer. Unlike adaptive lymphocytes, ILC2s do not express antigen-specific receptors. Consequently, the activity of ILC2s is dictated by the integration of signals they receive from their environment, subsequently influencing their effector functions. In cancer, where immune responses to tumors depend on how cells communicate with other cells, the capacity of ILC2s to respond to fluctuating signals may directly alter their antitumorigenic function, including a switch that converts them into a protumorigenic subset in the immunosuppressive tumor microenvironment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Ciancaglini C, Santopolo S, Martini S, Scordamaglia F, Pietropaolo G, Laffranchi M, et al. Macrophages regulate PD-1 and CTLA-4 expression on ILC2s and their responsiveness in the tumor microenvironment. Cell Mol Immunol. 2025;22:1491–1505.

  2. Jou E. Type 1 and type 2 cytokine-mediated immune orchestration in the tumor microenvironment and their therapeutic potential. Explor Target Antitumor Ther. 2023;4:474–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wagner M, Nishikawa H, Koyasu S. Reinventing type 2 immunity in cancer. Nature. 2025;637:296–303.

    Article  CAS  PubMed  Google Scholar 

  4. Jacquelot N, Seillet C, Vivier E, Belz GT. Innate lymphoid cells and cancer. Nat Immunol. 2022;23:371–9.

    Article  CAS  PubMed  Google Scholar 

  5. Asif S, Kinzel M, Vanderhyden B, Jacquelot N, Ardolino M. ILC2s in cancer: good, bad, or stay tuned? Trends Mol. Med. 2025. https://doi.org/10.1016/j.molmed.2025.06.010.

  6. Salimi M, Wang R, Yao X, Li X, Wang X, Hu Y, et al. Activated innate lymphoid cell populations accumulate in human tumor tissues. BMC Cancer. 2018;18:341.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Shen C, Liu C, Zhang Z, Ping Y, Shao J, Tian Y, et al. PD-1 affects the immunosuppressive function of group 2 innate lymphoid cells in human non-small cell lung cancer. Front Immunol. 2021;12. https://doi.org/10.3389/fimmu.2021.680055.

Download references

Acknowledgements

We thank the members of the Jacquelot and Ardolino laboratories for their insightful comments and discussion. Work in the Jacquelot and Ardolino laboratories is supported by an Alberta Cancer Foundation/Arnie Charbonneau Cancer Institute start-up package (to N.J.), a Canadian Cancer Society Emerging Scholar Research Grant (grant #708072, to N.J.), the Natural Sciences and Engineering Research Council of Canada (NSERC; to N.J.), the Dr. Robert C. Westbury Fund for Melanoma Research (to N.J.), the Canadian Foundation for Innovation (to N.J.), a Cancer Research Society and the Canadian Institutes of Health Research Institute for Cancer Research (grant #1274078, to N.J.), a Terry Fox Research Institute Program Projects Grant (TFRI Project #1153 to N.J. and M.A.), and the Canadian Institutes of Health Research (to M.A.). M. Kinzel was supported by a CIHR Master Award, Alberta Graduate Excellence Scholarships (AGES), and is supported by a CIHR Doctoral Award and an Izaak Walton Killam Doctoral Scholarship.

Author information

Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, Canada

    Megan Kinzel & Nicolas Jacquelot

  2. Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, AB, Canada

    Megan Kinzel & Nicolas Jacquelot

  3. Riddell Centre for Cancer Immunotherapy, Arnie Charbonneau Cancer Institute, Arthur J.E. Child Comprehensive Cancer Centre, Calgary, AB, Canada

    Megan Kinzel & Nicolas Jacquelot

  4. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada

    Dalia Ibrahim

  5. Cancer Research Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Dalia Ibrahim & Michele Ardolino

  6. Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada

    Dalia Ibrahim & Michele Ardolino

  7. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

    Michele Ardolino

  8. Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada

    Nicolas Jacquelot

  9. Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada

    Nicolas Jacquelot

Authors
  1. Megan Kinzel
    View author publications

    Search author on:PubMed Google Scholar

  2. Dalia Ibrahim
    View author publications

    Search author on:PubMed Google Scholar

  3. Michele Ardolino
    View author publications

    Search author on:PubMed Google Scholar

  4. Nicolas Jacquelot
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Nicolas Jacquelot.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kinzel, M., Ibrahim, D., Ardolino, M. et al. Feeling exhausted, no longer – macrophages keep type 2 innate lymphoid cells energized. Cell Mol Immunol 22, 1645–1647 (2025). https://doi.org/10.1038/s41423-025-01362-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41423-025-01362-y

Search

Advanced search

Quick links