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Ageing, immune fitness and cancer

Nature Reviews Cancer volume 25, pages 848–872 (2025)Cite this article

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Abstract

The immune system undergoes substantial changes throughout life, with ageing broadly impacting immune cell composition, function and regenerative capacity. Emerging evidence suggests that age-associated changes in immune fitness — the ability to respond to and eliminate infection, pathogens and malignancy while maintaining self-tolerance — reshape antitumour immunity and influence the efficacy of immunotherapies. Technological advances in high-dimensional immunoprofiling have begun to reveal the complex interplay between ageing, immune fitness and cancer biology, uncovering new therapeutic vulnerabilities and challenges. In this Review, we discuss recent insights derived from age-resolved immunoprofiling of the human tumour microenvironment, how ageing haematopoiesis affects immune cells that contribute to the microenvironment and impact cancer progression, and what is known from preclinical modelling about the functional consequences of immune ageing on tumour control. We further highlight emerging age-stratified analyses of treatment responses, which are beginning to inform hypotheses about how ageing shapes immunotherapy outcomes. Together, these perspectives provide a framework for integrating age as a critical biological variable, underscore the need to consider age in both preclinical models and clinical trial design, and identify key challenges and priorities for the field moving forward.

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Fig. 1: Immune status and function vary with age, impacting cancer development and progression.
Fig. 2: The age-related haematopoiesis–cancer axis.
Fig. 3: Age-associated barriers to effective antitumour immunity.
Fig. 4: Age-driven effects on the microenvironment that impact tumour immunity.

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Acknowledgements

K.A.L. is supported by the National Science Foundation (Graduate Research Fellowship Program). A.E.R. is supported by the National Institutes of Health (NIH) (K22CA266150), the Norn Group (Longevity Impetus Grant), the Elsa U. Pardee Foundation, and the American Federation for Aging Research/Glenn Foundation for Medical Research. P.v.G. is supported by the Ludwig Center at Harvard, the NIH (R33CA278393), the Starr Cancer Consortium, the Edward P. Evans Foundation, the Vera and Joseph Dresner Foundation, the MPN Research Foundation, a Research Scholar Grant from the American Cancer Society (RSG-24-1318769-01-CDP), a Hevolution/American Federation for Aging Research New Investigator Award, and the Brigham Research Institute. S.S.M. is supported by the Samuel Waxman Cancer Research Foundation in partnership with the Mark Foundation for Cancer Research, Victoria’s Secret Global Fund for Women’s Cancers Rising Innovator Research Grant in Partnership with Pelotonia & AACR (23-30-73-MCAL), Parker Institute for Cancer Immunotherapy, and National Cancer Institute (R01 CA279959).

Author information

Authors and Affiliations

  1. Hematology Division, Department of Medicine, Brigham & Women’s Hospital, Boston, MA, USA

    Melissa Dolan, Peter van Galen & Sandra S. McAllister

  2. Harvard Medical School, Boston, MA, USA

    Melissa Dolan, Peter van Galen & Sandra S. McAllister

  3. Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, MA, USA

    Kendra A. Libby & Alison E. Ringel

  4. Department of Biology, MIT, Cambridge, MA, USA

    Kendra A. Libby & Alison E. Ringel

  5. Koch Institute for Integrative Cancer Research, Cambridge, MA, USA

    Kendra A. Libby & Alison E. Ringel

  6. Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Peter van Galen & Sandra S. McAllister

  7. Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA

    Peter van Galen

  8. Harvard Stem Cell Institute, Cambridge, MA, USA

    Sandra S. McAllister

  9. Dana-Farber/Harvard Cancer Center, Boston, MA, USA

    Sandra S. McAllister

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  1. Melissa Dolan
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Contributions

All authors researched data for the article. M.D. and S.S.M. contributed substantially to the discussion of the content. All authors wrote the article. M.D. and S.S.M. reviewed and/or edited the manuscript before submission.

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Correspondence to Sandra S. McAllister.

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Nature Reviews Cancer thanks Jianwei Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Adipocytes

Specialized cells present in adipose or fat tissue that store lipid droplets, also referred to as lipocytes or fat cells.

Biological age

An estimate of an individual’s physiological state, based on molecular, cellular and tissue-level changes that reflect functional decline and accumulated damage, independent of chronological age.

Clonal haematopoiesis

Expansion of blood cells derived from a single haematopoietic stem cell that has acquired somatic mutations, reducing blood cell diversity.

Haematopoietic stem cells

(HSCs). Stem cells in the bone marrow with both self-renewal and oligopotent differentiation capacity that give rise to all blood cells, including myeloid and lymphoid lineages.

Immune-checkpoint inhibitor

(ICI). A type of immunotherapy (usually an antibody) designed to activate the immune system to attack cancer cells by binding to cell surface receptors or ligands that negatively regulate T cell activity.

Inflammageing

Ageing-associated chronic, low-grade inflammation, often marked by increased levels of circulating pro-inflammatory molecules and cells, independent of external stimuli (for example, bacteria, virus, antigens).

Mosaic loss of Y chromosome

A somatic mutation that generally occurs in older males, characterized by sporadic deletion of the Y chromosome in XY mammalian cells.

Natural killer (NK) cells

Innate immune lymphocytes that can detect and eliminate infected, diseased or malignant cells by releasing cytotoxic granules.

Neoantigens

Newly produced antigens or non-self proteins arising from genetic mutations, abnormal RNA splicing, altered post-translational modification, or integrated viral elements, capable of triggering an immune response.

Regulatory T (Treg) cells

A subset of CD4+ T cells characterized by FOXP3 expression and immunosuppressive functions that restrain autoimmunity and dampen antitumour immunity.

Resident memory T (TRM) cells

Long-lived T cells that remain in peripheral tissues to surveil previously encountered antigens, mounting rapid responses through cytolytic activity and immune cell recruitment.

Senescence-associated secretory phenotype

A hallmark of senescent cells, characterized by the secretion of immunomodulatory cytokines, chemokines, growth factors and matrix metalloproteinases.

Thymic involution

An age-related process whereby the thymus progressively loses tissue mass, resulting in diminished production and maturation of T cells.

Tumour-associated macrophages

(TAMs). Phenotypically and functionally diverse macrophages within solid tumours capable of promoting or suppressing immune responses (thereby either supporting or inhibiting tumour growth and metastasis), originating from circulating monocytes or tissue-resident macrophages.

Tumour-associated neutrophils

Neutrophils found within solid tumours that can either promote tumour growth through immunosuppression or inhibit it by killing tumour cells and, unlike their non-cancer-associated counterparts, can persist in the tumour microenvironment.

Tumour-infiltrating lymphocytes

(TILs). Lymphocytes, including T cells, B cells and natural killer cells, that reside near or within tumour cell-dense areas of solid tumours that contribute to antitumour immunity and serve as important biomarkers in cancer treatment.

Type 1 conventional dendritic cells

(cDC1s). A specialized dendritic cell subset that selectively expresses the chemokine receptor XCR1 and C-type lectin receptor CLEC9A in humans and excels at cross-presenting antigens to cytotoxic CD8+ T cells, playing key roles in antitumour and anti-viral immunity.

X-chromosome inactivation

A process whereby one X-chromosome copy is transcriptionally silenced in mammalian cells containing two X chromosomes.

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Dolan, M., Libby, K.A., Ringel, A.E. et al. Ageing, immune fitness and cancer. Nat Rev Cancer 25, 848–872 (2025). https://doi.org/10.1038/s41568-025-00858-z

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