January 15, 2026

Ageing, immune fitness and cancer

Ageing, immune fitness and cancer
  • Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 74, 12–49 (2024).

    PubMed 

    Google Scholar 

  • Dorshkind, K., Montecino-Rodriguez, E. & Signer, R. A. J. The ageing immune system: is it ever too old to become young again? Nat. Rev. Immunol. 9, 57–62 (2009).

    PubMed 
    CAS 

    Google Scholar 

  • Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 74, 229–263 (2024).

    PubMed 

    Google Scholar 

  • VanderWalde, N. A. et al. Disparities in older adult accrual to cancer trials: analysis from the Alliance for Clinical Trials in Oncology (A151736). J. Geriatr. Oncol. 13, 20–26 (2022).

    PubMed 
    CAS 

    Google Scholar 

  • Freedman, R. A. et al. Breast cancer-specific survival by age: worse outcomes for the oldest patients. Cancer 124, 2184–2191 (2018).

    PubMed 
    CAS 

    Google Scholar 

  • Lancaster, J. N. Aging of lymphoid stromal architecture impacts immune responses. Semin. Immunol. 70, 101817 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Han, S., Georgiev, P., Ringel, A. E., Sharpe, A. H. & Haigis, M. C. Age-associated remodeling of T cell immunity and metabolism. Cell Metab. 35, 36–55 (2023).

    PubMed 
    CAS 

    Google Scholar 

  • Mogilenko, D. A., Shchukina, I. & Artyomov, M. N. Immune ageing at single-cell resolution. Nat. Rev. Immunol. 22, 484–498 (2022).

    PubMed 
    CAS 

    Google Scholar 

  • Swanton, C. et al. Embracing cancer complexity: hallmarks of systemic disease. Cell 187, 1589–1616 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Kalathoor, S. et al. Representation of women in clinical trials supporting FDA-approval of contemporary cancer therapies. Int. J. Cancer 155, 1958–1968 (2024).

    PubMed 
    CAS 

    Google Scholar 

  • O’Rourke, K. New FDA guidance recommends increasing the number of older adults in cancer clinical trials: the guidance is intended to assist in evaluating cancer therapies in adults aged 65 years and older: the guidance is intended to assist in evaluating cancer therapies in adults aged 65 years and older. Cancer 128, 2397–2398 (2022).

    PubMed 

    Google Scholar 

  • Lee, W., Wang, Z., Saffern, M., Jun, T. & Huang, K.-L. Genomic and molecular features distinguish young adult cancer from later-onset cancer. Cell Rep. 37, 110005 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zhou, A., Zhang, D., Kang, X. & Brooks, J. D. Identification of age- and immune-related gene signatures for clinical outcome prediction in lung adenocarcinoma. Cancer Med. 12, 17475–17490 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wu, Y. et al. Comprehensive transcriptome profiling in elderly cancer patients reveals aging-altered immune cells and immune checkpoints. Int. J. Cancer 144, 1657–1663 (2019).

    PubMed 
    CAS 

    Google Scholar 

  • Erbe, R. et al. Evaluating the impact of age on immune checkpoint therapy biomarkers. Cell Rep. 36, 109599 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Kugel, C. H. et al. Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin. Cancer Res. 24, 5347–5356 (2018).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Chen, L., Zhang, M., Zhou, J., Zhang, L. & Liang, C. Establishment of an age- and tumor microenvironment-related gene signature for survival prediction in prostate cancer. Cancer Med. 11, 4374–4388 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Shah, Y. et al. Pan-cancer analysis reveals molecular patterns associated with age. Cell Rep. 37, 110100 (2021).

    PubMed 
    CAS 

    Google Scholar 

  • Park, M. D. et al. Hematopoietic aging promotes cancer by fueling IL-1α-driven emergency myelopoiesis. Science 386, eadn0327 (2024). This study shows how IL-1α alters haematopoietic stem and progenitor cells in the ageing bone marrow to facilitate myeloid cell production and immunosuppression in lung tumours.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Qing, T. et al. Molecular differences between younger versus older ER-positive and HER2-negative breast cancers. NPJ Breast Cancer 8, 119 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Takada, K. et al. Differences in tumor-infiltrating lymphocyte density and prognostic factors for breast cancer by patient age. World J. Surg. Oncol. 20, 38 (2022).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Buja, A. et al. Cutaneous melanoma in older patients. BMC Geriatr. 24, 232 (2024).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Brummel, K., Eerkens, A. L., de Bruyn, M. & Nijman, H. W. Tumour-infiltrating lymphocytes: from prognosis to treatment selection. Br. J. Cancer 128, 451–458 (2023).

    PubMed 
    CAS 

    Google Scholar 

  • Jeske, S. S. et al. Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma. Immun. Ageing 17, 3 (2020).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Newman, A. M. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453–457 (2015).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Yoshihara, K. et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun. 4, 2612 (2013).

    PubMed 

    Google Scholar 

  • Racle, J. & Gfeller, D. EPIC: a tool to estimate the proportions of different cell types from bulk gene expression data. Methods Mol. Biol. 2120, 233–248 (2020).

    PubMed 
    CAS 

    Google Scholar 

  • Li, T. et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 77, e108–e110 (2017).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Im, Y. & Kim, Y. A comprehensive overview of RNA deconvolution methods and their application. Mol. Cell 46, 99–105 (2023).

    CAS 

    Google Scholar 

  • Zhang, Z. et al. A panoramic view of cell population dynamics in mammalian aging. Science eadn3949, 387 (2025).

    Google Scholar 

  • Tabula Muris Consortium. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020).

    Google Scholar 

  • Mogilenko, D. A. et al. Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity 54, 99–115.e12 (2021). This study used a combination of scRNA-seq, TCR and B cell receptor analysis to assess the immune profile in multiple organs of aged mice and discovered a clonal GZMK+ CD8+ T cell population with pro-inflammatory activity that was also found in the circulation of older adults.

    PubMed 
    CAS 

    Google Scholar 

  • Angarola, B. L. et al. Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer. Nat. Aging 5, 122–143 (2024). This study demonstrated that distinct T cell subsets and macrophages expand in the aged mammary gland in mice and that transcriptional signatures of ageing mammary cells are enriched in human breast tumours.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Tiberti, S. et al. GZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in non-metastatic colorectal tumors and predict poor clinical outcome. Nat. Commun. 13, 6752 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Lan, F. et al. GZMK-expressing CD8+ T cells promote recurrent airway inflammatory diseases. Nature 638, 490–498 (2025).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wells, S. B. et al. Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age. Preprint at bioRxiv (2024). This study uses CITE-seq to provide a comprehensive analysis of the human immune system across various tissues and donor ages, demonstrating that age-related changes in immune homeostasis are tissue specific.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Wu, S. Z. et al. A single-cell and spatially resolved atlas of human breast cancers. Nat. Genet. 53, 1334–1347 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Parsons, A. et al. Cell populations in human breast cancers are molecularly and biologically distinct with age. Preprint at Res. Sq. (2024). This is the first study to show subtype-specific age-related changes in the TIME of human breast cancer at single-cell resolution.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Salcher, S. et al. High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer. Cancer Cell 40, 1503–1520.e8 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Safina, K. & van Galen, P. New frameworks for hematopoiesis derived from single-cell genomics. Blood 144, 1039–1047 (2024).

    PubMed 
    CAS 

    Google Scholar 

  • Weisberg, S. P., Ural, B. B. & Farber, D. L. Tissue-specific immunity for a changing world. Cell 184, 1517–1529 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • McAllister, S. S. & Weinberg, R. A. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat. Cell Biol. 16, 717–727 (2014).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Cao, R., Thatavarty, A. & King, K. Y. Forged in the fire: lasting impacts of inflammation on hematopoietic progenitors. Exp. Hematol. 134, 104215 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Yang, D. & de Haan, G. Inflammation and aging of hematopoietic stem cells in their niche. Cells 10, 1849 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Pietras, E. M. Inflammation: a key regulator of hematopoietic stem cell fate in health and disease. Blood 130, 1693–1698 (2017).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Fotopoulou, F., Rodríguez-Correa, E., Dussiau, C. & Milsom, M. D. Reconsidering the usual suspects in age-related hematologic disorders: is stem cell dysfunction a root cause of aging? Exp. Hematol. 143, 104698 (2025).

    PubMed 
    CAS 

    Google Scholar 

  • Kovtonyuk, L. V. et al. IL-1 mediates microbiome-induced inflammaging of hematopoietic stem cells in mice. Blood 139, 44–58 (2022).

    PubMed 
    CAS 

    Google Scholar 

  • Caiado, F. & Manz, M. G. IL-1 in aging and pathologies of hematopoietic stem cells. Blood 144, 368–377 (2024).

    PubMed 
    CAS 

    Google Scholar 

  • Jergović, M. et al. IL-6 can singlehandedly drive many features of frailty in mice. GeroScience 43, 539–549 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Alvarez-Rodríguez, L., López-Hoyos, M., Muñoz-Cacho, P. & Martínez-Taboada, V. M. Aging is associated with circulating cytokine dysregulation. Cell. Immunol. 273, 124–132 (2012).

    PubMed 

    Google Scholar 

  • Albani, D. et al. Interleukin-6 plasma level increases with age in an Italian elderly population (“The Treviso Longeva”-Trelong-study) with a sex-specific contribution of rs1800795 polymorphism. Age 31, 155–162 (2009).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Beharka, A. A. et al. Interleukin-6 production does not increase with age. J. Gerontol. A Biol. Sci. Med. Sci. 56, B81–B88 (2001).

    PubMed 
    CAS 

    Google Scholar 

  • Tylutka, A., Walas, Ł. & Zembron-Lacny, A. Level of IL-6, TNF, and IL-1β and age-related diseases: a systematic review and meta-analysis. Front. Immunol. 15, 1330386 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Pietras, E. M. et al. Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat. Cell Biol. 18, 607–618 (2016).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Chavez, J. S. et al. PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress. J. Exp. Med. 218, e20201169 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Frisch, B. J. et al. Aged marrow macrophages expand platelet-biased hematopoietic stem cells via Interleukin1B. JCI Insight 5, e124213 (2019).

    PubMed 

    Google Scholar 

  • Ho, Y.-H. et al. Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging. Cell Stem Cell 25, 407–418.e6 (2019).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zhao, J. L. et al. Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell 14, 445–459 (2014).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    PubMed 
    CAS 

    Google Scholar 

  • Ridker, P. M. et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017).

    PubMed 
    CAS 

    Google Scholar 

  • Lythgoe, M. P. & Prasad, V. Repositioning canakinumab for non-small cell lung cancer-important lessons for drug repurposing in oncology. Br. J. Cancer 127, 785–787 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • US National Library of Medicine. ClinicalTrials.gov (2021).

  • Bruunsgaard, H., Skinhøj, P., Pedersen, A. N., Schroll, M. & Pedersen, B. K. Ageing, tumour necrosis factor-alpha (TNF-α) and atherosclerosis. Clin. Exp. Immunol. 121, 255–260 (2000).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • SanMiguel, J. M. et al. Distinct tumor necrosis factor alpha receptors dictate stem cell fitness versus lineage output in Dnmt3a-mutant clonal hematopoiesis. Cancer Discov. 12, 2763–2773 (2022). This study decouples the fitness and lineage bias effects of age-associated TNF signalling in DNMT3A-mutant clonal haematopoiesis.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Liu, Z. G. Molecular mechanism of TNF signaling and beyond. Cell Res. 15, 24–27 (2005).

    PubMed 
    CAS 

    Google Scholar 

  • Yamashita, M. & Passegué, E. TNF-α coordinates hematopoietic stem cell survival and myeloid regeneration. Cell Stem Cell 25, 357–372.e7 (2019).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • He, H. et al. Aging-induced IL27Ra signaling impairs hematopoietic stem cells. Blood 136, 183–198 (2020).

    PubMed 

    Google Scholar 

  • Jakobsen, N. A. et al. Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging. Cell Stem Cell 31, 1127–1144.e17 (2024). Although bone marrow HSCs from individuals with CHIP show increased inflammatory gene expression compared with individuals without CHIP, within the CHIP marrow, DNMT3A-mutant and TET2-mutant HSCs have attenuated inflammatory signalling compared with wild-type HSCs.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Cheong, J.-G. et al. Epigenetic memory of coronavirus infection in innate immune cells and their progenitors. Cell 186, 3882–3902.e24 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zeng, A. G. X. et al. Identification of a human hematopoietic stem cell subset that retains memory of inflammatory stress. Preprint at bioRxiv (2023). This study shows the presence of multiple HSC subsets in humans, including an inflammatory memory HSC subset induced by inflammatory stress stimuli.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Kain, B. N. et al. Hematopoietic stem and progenitor cells confer cross-protective trained immunity in mouse models. iScience 26, 107596 (2023). This study establishes that inflammatory memory can be encoded at the stem cell level using transplantation of highly purified inflammation-exposed mouse HSCs.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Mills, T. S. et al. A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice. Cell Stem Cell 31, 1630–1649.e8 (2024).

    PubMed 
    CAS 

    Google Scholar 

  • Shiozawa, S. et al. Age distribution of circulating alpha-interferon. Experientia 45, 764–765 (1989).

    PubMed 
    CAS 

    Google Scholar 

  • Helbling, P. M. et al. Global transcriptomic profiling of the bone marrow stromal microenvironment during postnatal development, aging, and inflammation. Cell Rep. 29, 3313–3330.e4 (2019).

    PubMed 
    CAS 

    Google Scholar 

  • Benayoun, B. A. et al. Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses. Genome Res. 29, 697–709 (2019).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Havas, A. P. et al. Activated interferon signaling suppresses age-dependent liver cancer. Preprint at bioRxiv (2024).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Baldridge, M. T., King, K. Y., Boles, N. C., Weksberg, D. C. & Goodell, M. A. Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection. Nature 465, 793–797 (2010).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Essers, M. A. G. et al. IFNα activates dormant haematopoietic stem cells in vivo. Nature 458, 904–908 (2009).

    PubMed 
    CAS 

    Google Scholar 

  • Bogeska, R. et al. Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell Stem Cell 29, 1273–1284.e8 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Kristinsson, S. Y. et al. Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes. J. Clin. Oncol. 29, 2897–2903 (2011). This longitudinal population study links a history of infections or autoimmune diseases to an increased risk of myelodysplastic syndromes and acute myeloid leukaemia.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Rönkkö, R. M., Nevala, A. O., Pitkäniemi, J. M., Wartiovaara-Kautto, U. M. & Malila, N. K. Subsequent malignant neoplasms after primary hematological malignancy in adult patients. Int. J. Cancer 155, 1007–1013 (2024).

    PubMed 

    Google Scholar 

  • Lenz, A., Franklin, G. A. & Cheadle, W. G. Systemic inflammation after trauma. Injury 38, 1336–1345 (2007).

    PubMed 

    Google Scholar 

  • Eskesen, T. O. et al. Association of trauma with long-term risk of death and immune-mediated or cancer disease in same-sex twins. JAMA Surg. 158, 738–745 (2023).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Mitchell, E. et al. Clonal dynamics of haematopoiesis across the human lifespan. Nature 606, 343–350 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Weng, C. et al. Deciphering cell states and genealogies of human haematopoiesis. Nature 627, 389–398 (2024). This study used multimodal single-cell analysis to quantify HSC clones and their output from human bone marrow samples.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Razavi, P. et al. High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. Nat. Med. 25, 1928–1937 (2019).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Young, A. L., Challen, G. A., Birmann, B. M. & Druley, T. E. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7, 12484 (2016).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Belizaire, R., Wong, W. J., Robinette, M. L. & Ebert, B. L. Clonal haematopoiesis and dysregulation of the immune system. Nat. Rev. Immunol. 23, 595–610 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Caiado, F. et al. Aging drives Tet2+/− clonal hematopoiesis via IL-1 signaling. Blood 141, 886–903 (2023).

    PubMed 
    CAS 

    Google Scholar 

  • Quin, C. et al. Chronic TNF in the aging microenvironment exacerbates Tet2 loss-of-function myeloid expansion. Blood Adv. 8, 4169–4180 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zioni, N. et al. Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis. Nat. Commun. 14, 2070 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Liao, M. et al. Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis. Acta Pharm. Sin. B. 12, 678–691 (2022).

    PubMed 
    CAS 

    Google Scholar 

  • Heimlich, J. B. et al. Multiomic profiling of human clonal hematopoiesis reveals genotype and cell-specific inflammatory pathway activation. Blood Adv. 8, 3665–3678 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Arends, C. M. et al. Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis. Leukemia 32, 1908–1919 (2018).

    PubMed 
    CAS 

    Google Scholar 

  • Buscarlet, M. et al. Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A. Blood 132, 277–280 (2018).

    PubMed 
    CAS 

    Google Scholar 

  • Kasbekar, M., Mitchell, C. A., Proven, M. A. & Passegué, E. Hematopoietic stem cells through the ages: a lifetime of adaptation to organismal demands. Cell Stem Cell 30, 1403–1420 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Colom Díaz, P. A., Mistry, J. J. & Trowbridge, J. J. Hematopoietic stem cell aging and leukemia transformation. Blood 142, 533–542 (2023).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Yamamoto, R. et al. Large-scale clonal analysis resolves aging of the mouse hematopoietic stem cell compartment. Cell Stem Cell 22, 600–607.e4 (2018).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Young, K. et al. Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging. Cell Stem Cell 28, 1473–1482.e7 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Nishi, K. et al. Alteration of long and short-term hematopoietic stem cell ratio causes myeloid-biased hematopoiesis. eLife (2025).

    Google Scholar 

  • Tharmapalan, V. & Wagner, W. Biomarkers for aging of blood — how transferable are they between mice and humans? Exp. Hematol. 140, 104600 (2024).

    PubMed 
    CAS 

    Google Scholar 

  • Kuranda, K. et al. Age-related changes in human hematopoietic stem/progenitor cells. Aging Cell 10, 542–546 (2011).

    PubMed 
    CAS 

    Google Scholar 

  • Amoah, A. et al. Aging of human hematopoietic stem cells is linked to changes in Cdc42 activity. Haematologica 107, 393–402 (2022).

    PubMed 
    CAS 

    Google Scholar 

  • Pang, W. W. et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc. Natl Acad. Sci. USA 108, 20012–20017 (2011).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Alpert, A. et al. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat. Med. 25, 487–495 (2019). This study was the first to leverage immune-omics population data in a longitudinal framework to develop an immune ageing score, IMM-AGE, which is distinct from chronological age and predicts all-cause mortality, outperforming other established risk assessment algorithms.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Chang, S.-T. et al. Age-dependent immune profile in healthy individuals: an original study, systematic review and meta-analysis. Immun. Ageing 21, 75 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Huang, Z. et al. Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis. Proc. Natl Acad. Sci. USA 118, e2023216118 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Burel, J. G. et al. An integrated workflow to assess technical and biological variability of cell population frequencies in human peripheral blood by flow cytometry. J. Immunol. 198, 1748–1758 (2017).

    PubMed 
    CAS 

    Google Scholar 

  • Márquez, E. J. et al. Sexual-dimorphism in human immune system aging. Nat. Commun. 11, 751 (2020).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Luo, O. J. et al. Multidimensional single-cell analysis of human peripheral blood reveals characteristic features of the immune system landscape in aging and frailty. Nat. Aging 2, 348–364 (2022).

    PubMed 
    CAS 

    Google Scholar 

  • Filippov, I., Schauser, L. & Peterson, P. An integrated single-cell atlas of blood immune cells in aging. NPJ Aging 10, 59 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Furer, N. et al. A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics. Nat. Med. 31, 2442–2451 (2025).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • van Bergen, M. G. J. M. et al. Clonal hematopoiesis and myeloid skewing in older population-based individuals. Am. J. Hematol. 99, 2402–2405 (2024).

    PubMed 

    Google Scholar 

  • Eller, L. A. et al. Reference intervals in healthy adult Ugandan blood donors and their impact on conducting international vaccine trials. PLoS One 3, e3919 (2008).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Peng, L. et al. Effects of biological variations on platelet count in healthy subjects in China. Thromb. Haemost. 91, 367–372 (2004).

    PubMed 
    CAS 

    Google Scholar 

  • Cohen, N. M. et al. Personalized lab test models to quantify disease potentials in healthy individuals. Nat. Med. 27, 1582–1591 (2021). This study takes an original approach to predict disease by large-scale mining of laboratory tests from electronic health record data mining.

    PubMed 
    CAS 

    Google Scholar 

  • Mittelbrunn, M. & Kroemer, G. Hallmarks of T cell aging. Nat. Immunol. 22, 687–698 (2021).

    PubMed 
    CAS 

    Google Scholar 

  • Britanova, O. V. et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J. Immunol. 192, 2689–2698 (2014).

    PubMed 
    CAS 

    Google Scholar 

  • Nikolich-Zugich, J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat. Rev. Immunol. 8, 512–522 (2008).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Yager, E. J. et al. Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J. Exp. Med. 205, 711–723 (2008).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Cicin-Sain, L. et al. Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates. J. Immunol. 184, 6739–6745 (2010).

    PubMed 
    CAS 

    Google Scholar 

  • Adeegbe, D., Matsutani, T., Yang, J., Altman, N. H. & Malek, T. R. CD4+ CD25+ Foxp3+ T regulatory cells with limited TCR diversity in control of autoimmunity. J. Immunol. 184, 56–66 (2010).

    PubMed 
    CAS 

    Google Scholar 

  • Lorenzi, A. R. et al. Determination of thymic function directly from peripheral blood: a validated modification to an established method. J. Immunol. Methods 339, 185–194 (2008).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Nishida, J. et al. Peripheral blood TCR clonotype diversity as an age-associated marker of breast cancer progression. Proc. Natl Acad. Sci. USA 120, e2316763120 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Manuel, M. et al. Lymphopenia combined with low TCR diversity (divpenia) predicts poor overall survival in metastatic breast cancer patients. Oncoimmunology 1, 432–440 (2012).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Luo, W. et al. Normalization of T cell receptor repertoire diversity in patients with advanced colorectal cancer who responded to chemotherapy. Cancer Sci. 102, 706–712 (2011).

    PubMed 
    CAS 

    Google Scholar 

  • Salih, Z. et al. T cell immune awakening in response to immunotherapy is age-dependent. Eur. J. Cancer 162, 11–21 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • McAllister, S. S. et al. Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 133, 994–1005 (2008).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Direkze, N. C. et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res. 64, 8492–8495 (2004).

    PubMed 
    CAS 

    Google Scholar 

  • Worthley, D. L. et al. Human gastrointestinal neoplasia-associated myofibroblasts can develop from bone marrow-derived cells following allogeneic stem cell transplantation. Stem Cell 27, 1463–1468 (2009).

    CAS 

    Google Scholar 

  • Miller, T. E. et al. Mitochondrial variant enrichment from high-throughput single-cell RNA sequencing resolves clonal populations. Nat. Biotechnol. 40, 1030–1034 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Miller, T. E. et al. Programs, origins, and niches of immunomodulatory myeloid cells in gliomas. Nature 640, 1072–1082 (2025).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Shlush, L. I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Severson, E. A. et al. Detection of clonal hematopoiesis of indeterminate potential in clinical sequencing of solid tumor specimens. Blood 131, 2501–2505 (2018).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Swisher, E. M. et al. Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA Oncol. 2, 370–372 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Coombs, C. C. et al. Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next-generation sequencing assays. Clin. Cancer Res. 24, 5918–5924 (2018).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zajkowicz, A. et al. Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. Br. J. Cancer 112, 1114–1120 (2015).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Mayerhofer, C. et al. Clonal hematopoiesis in older patients with breast cancer receiving chemotherapy. J. Natl Cancer Inst. 115, 981–988 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ptashkin, R. N. et al. Prevalence of clonal hematopoiesis mutations in tumor-only clinical genomic profiling of solid tumors. JAMA Oncol. 4, 1589–1593 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Comen, E. A. et al. Evaluating clonal hematopoiesis in tumor-infiltrating leukocytes in breast cancer and secondary hematologic malignancies. J. Natl Cancer Inst. 112, 107–110 (2020).

    PubMed 

    Google Scholar 

  • Bolton, K. L. et al. Managing clonal hematopoiesis in patients with solid tumors. J. Clin. Oncol. 37, 7–11 (2019).

    PubMed 
    CAS 

    Google Scholar 

  • Coombs, C. C. et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21, 374–382.e4 (2017).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Kleppe, M. et al. Somatic mutations in leukocytes infiltrating primary breast cancers. NPJ Breast Cancer 1, 15005 (2015).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Marchetti, A. et al. Impact of clonal hematopoiesis of indeterminate potential on hepatocellular carcinoma in individuals with steatotic liver disease. Hepatology 80, 816–827 (2024).

    PubMed 

    Google Scholar 

  • Buttigieg, M. M., Vlasschaert, C., Bick, A. G., Vanner, R. J. & Rauh, M. J. Inflammatory reprogramming of the solid tumor microenvironment by infiltrating clonal hematopoiesis is associated with adverse outcomes. Cell Rep. Med. 6, 101989 (2025).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Pich, O. et al. Tumor-infiltrating clonal hematopoiesis. N. Engl. J. Med. 392, 1594–1608 (2025). This study shows that the presence of TI-CH in patients with NSCLC associates with increased recurrence and demonstrates that TI-CH can remodel the TIME and promote tumour organoid growth in mice.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Feng, Y. et al. Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer. J. Exp. Med. 220, e20230011 (2023). This is the first demonstration of a causal relationship between a CHIP mutation in HSCs and the progression of a solid tumour.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • McAllister, S. S. & Weinberg, R. A. Tumor-host interactions: a far-reaching relationship. J. Clin. Oncol. 28, 4022–4028 (2010).

    PubMed 

    Google Scholar 

  • Redig, A. J. & McAllister, S. S. Breast cancer as a systemic disease: a view of metastasis. J. Intern. Med. 274, 113–126 (2013).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Elkabets, M. et al. Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. J. Clin. Invest. 121, 784–799 (2011).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Medrek, C., Pontén, F., Jirström, K. & Leandersson, K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer 12, 306 (2012).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Bateman, A., Cheung, S. T. & Bennett, H. P. J. A brief overview of progranulin in health and disease. Methods Mol. Biol. 1806, 3–15 (2018).

    PubMed 
    CAS 

    Google Scholar 

  • Marsh, T. et al. Hematopoietic age at onset of triple-negative breast cancer dictates disease aggressiveness and progression. Cancer Res. 76, 2932–2943 (2016). This study was the first to demonstrate that age alters the haematopoiesis–cancer axis, showing that bone marrow-derived haematopoietic cells from young mice promote TNBC progression by supporting a tumour-supportive microenvironment, while ageing diminishes their pro-tumorigenic capacity.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Mitchell, C. A. et al. Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing. Nat. Cell Biol. 25, 30–41 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ho, T. T. et al. Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions. J. Exp. Med. 218, e20210223 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ramalingam, P. et al. Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA damage response. Nat. Commun. 14, 2018 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Dellorusso, P. V. et al. Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells. Cell Stem Cell 31, 1020–1037.e9 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ross, J. B. et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature 628, 162–170 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wang, Y. et al. Reducing functionally defective old HSCs alleviates aging-related phenotypes in old recipient mice. Cell Res. 35, 45–58 (2025).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wang, S., Lai, X., Deng, Y. & Song, Y. Correlation between mouse age and human age in anti-tumor research: significance and method establishment. Life Sci. 242, 117242 (2020).

    PubMed 
    CAS 

    Google Scholar 

  • Anczuków, O. et al. Challenges and opportunities for modeling aging and cancer. Cancer Cell 41, 641–645 (2023).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Yuan, R. et al. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8, 277–287 (2009).

    PubMed 
    CAS 

    Google Scholar 

  • Brayton, C. F., Treuting, P. M. & Ward, J. M. Pathobiology of aging mice and GEM: background strains and experimental design. Vet. Pathol. 49, 85–105 (2012).

    PubMed 
    CAS 

    Google Scholar 

  • Hale, J. S., Boursalian, T. E., Turk, G. L. & Fink, P. J. Thymic output in aged mice. Proc. Natl Acad. Sci. USA 103, 8447–8452 (2006).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Sceneay, J. et al. Interferon signaling is diminished with age and is associated with immune checkpoint blockade efficacy in triple-negative breast cancer. Cancer Discov. 9, 1208–1227 (2019). This study demonstrated that aged-related immune dysfunction limits immune-checkpoint blockade efficacy in TNBC, with parallel deficits observed in both aged mice and older patients with TNBC, highlighting age as a critical determinant of ICI responses.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zhivaki, D. et al. Correction of age-associated defects in dendritic cells enables CD4+ T cells to eradicate tumors. Cell 187, 3888–3903.e18 (2024). This study demonstrated that hyperactivating DCs using a vaccine adjuvant overcomes ageing-related deficiencies in antitumour immunity by improving DC migration and induction of cytotoxic TH1 CD4+ T cells in aged mice.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Chen, A. C. Y. et al. The aged tumor microenvironment limits T cell control of cancer. Nat. Immunol. 25, 1033–1045 (2024). This study used scRNAseq to reveal an age-associated dysfunctional CD8+ T cell subset that promotes tumour progression in aged mice, and showed that impaired NK–DC–CD8+ T cell crosstalk can be restored by myeloid cell activation using a CD40 agonist.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Georgiev, P. et al. Age-associated contraction of tumor-specific T cells impairs antitumor immunity. Cancer Immunol. Res. 12, 1525–1541 (2024). This study established that aged mice have fewer tumour antigen-specific CD8+ T cells and that transferring antigen-specific CD8+ T cells from young mice to aged mice could improve PD1-checkpoint blockade efficacy.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Sitnikova, S. I. et al. Age-induced changes in anti-tumor immunity alter the tumor immune infiltrate and impact response to immuno-oncology treatments. Front. Immunol. 14, 1258291 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Norian, L. A. & Allen, P. M. No intrinsic deficiencies in CD8+ T cell-mediated antitumor immunity with aging. J. Immunol. 173, 835–844 (2004).

    PubMed 
    CAS 

    Google Scholar 

  • Lee-Chang, C. et al. Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity. Blood 124, 1450–1459 (2014).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zhang, C. et al. Single-cell sequencing reveals antitumor characteristics of intratumoral immune cells in old mice. J. Immunother. Cancer 9, e002809 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Duong, L. et al. Macrophage depletion in elderly mice improves response to tumor immunotherapy, increases anti-tumor T cell activity and reduces treatment-induced cachexia. Front. Genet. 9, 526 (2018).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Oh, J., Magnuson, A., Benoist, C., Pittet, M. J. & Weissleder, R. Age-related tumor growth in mice is related to integrin α4 in CD8+ T cells. JCI Insight 3, e122961 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Henry, C. J. & DeGregori, J. Modelling the ageing dependence of cancer evolutionary trajectories. Nat. Rev. Cancer (2025).

    PubMed 

    Google Scholar 

  • Mellman, I., Chen, D. S., Powles, T. & Turley, S. J. The cancer-immunity cycle: indication, genotype, and immunotype. Immunity 56, 2188–2205 (2023). This publication updates the foundational cancer-immunity cycle framework, emphasizing the growing complexity of tumour–immune interactions, the dual roles of various immune cell types in promoting or suppressing antitumour responses, and the relevance of categorizing tumours by their immunological phenotype, or ‘immunotype’.

    PubMed 
    CAS 

    Google Scholar 

  • Grizzle, W. E. et al. Age-related increase of tumor susceptibility is associated with myeloid-derived suppressor cell mediated suppression of T cell cytotoxicity in recombinant inbred BXD12 mice. Mech. Ageing Dev. 128, 672–680 (2007).

    PubMed 
    CAS 

    Google Scholar 

  • Kallies, A. & Good-Jacobson, K. L. Transcription factor T-bet orchestrates lineage development and function in the immune system. Trends Immunol. 38, 287–297 (2017).

    PubMed 
    CAS 

    Google Scholar 

  • Tsukamoto, H., Senju, S., Matsumura, K., Swain, S. L. & Nishimura, Y. IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age. Nat. Commun. 6, 6702 (2015). This study demonstrated that elevated IL-6 impairs CD4+ T cell differentiation and CD8+ T cell-mediated tumour control in aged mice.

    PubMed 
    CAS 

    Google Scholar 

  • Jagger, A., Shimojima, Y., Goronzy, J. J. & Weyand, C. M. Regulatory T cells and the immune aging process: a mini-review. Gerontology 60, 130–137 (2014).

    PubMed 
    CAS 

    Google Scholar 

  • Elyahu, Y. et al. Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci. Adv. 5, eaaw8330 (2019).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Okła, K., Farber, D. L. & Zou, W. Tissue-resident memory T cells in tumor immunity and immunotherapy. J. Exp. Med. 218, e20201605 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Malik, B. T. et al. Resident memory T cells in the skin mediate durable immunity to melanoma. Sci. Immunol. 2, eaam6346 (2017).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Gavil, N. V., Cheng, K. & Masopust, D. Resident memory T cells and cancer. Immunity 57, 1734–1751 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Luoma, A. M. et al. Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy. Cell 185, 2918–2935.e29 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Pei, S. et al. Age-related decline in CD8+ tissue resident memory T cells compromises antitumor immunity. Nat. Aging 4, 1828–1844 (2024). This study showed reduced CD8+ TRM cells in the lung and liver of aged mice, leading to impaired antitumour immune control.

    PubMed 
    CAS 

    Google Scholar 

  • Schenkel, J. M. & Masopust, D. Tissue-resident memory T cells. Immunity 41, 886–897 (2014).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Pei, S. et al. BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy. J. Exp. Med. 218, e20202144 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • du Halgouet, A. et al. Multimodal profiling reveals site-specific adaptation and tissue residency hallmarks of γδ T cells across organs in mice. Nat. Immunol. 25, 343–356 (2024).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Thome, J. J. C. et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159, 814–828 (2014).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • de Mol, J., Kuiper, J., Tsiantoulas, D. & Foks, A. C. The dynamics of B cell aging in health and disease. Front. Immunol. 12, 733566 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, E. et al. Roles and mechanisms of tumour-infiltrating B cells in human cancer: a new force in immunotherapy. Biomark. Res. 11, 28 (2023).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, P., Chu, Y. & Liu, R. Tumour-reactive plasma cells in antitumour immunity: current insights and future prospects. Immunother. Adv. 4, ltae003 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Singh, R., Kim, Y.-H., Lee, S.-J., Eom, H.-S. & Choi, B. K. 4-1BB immunotherapy: advances and hurdles. Exp. Mol. Med. 56, 32–39 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wolf, N. K., Kissiov, D. U. & Raulet, D. H. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat. Rev. Immunol. 23, 90–105 (2023).

    PubMed 
    CAS 

    Google Scholar 

  • Hazeldine, J. & Lord, J. M. The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res. Rev. 12, 1069–1078 (2013).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 12, 1088 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Böttcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037.e14 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Guimond, M. et al. In vivo role of Flt3 ligand and dendritic cells in NK cell homeostasis. J. Immunol. 184, 2769–2775 (2010).

    PubMed 
    CAS 

    Google Scholar 

  • van Vlerken-Ysla, L., Tyurina, Y. Y., Kagan, V. E. & Gabrilovich, D. I. Functional states of myeloid cells in cancer. Cancer Cell 41, 490–504 (2023).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Jackaman, C. et al. Aging and cancer: the role of macrophages and neutrophils. Ageing Res. Rev. 36, 105–116 (2017).

    PubMed 
    CAS 

    Google Scholar 

  • Jackaman, C. & Nelson, D. J. Are macrophages, myeloid derived suppressor cells and neutrophils mediators of local suppression in healthy and cancerous tissues in aging hosts? Exp. Gerontol. 54, 53–57 (2014).

    PubMed 
    CAS 

    Google Scholar 

  • Li, Y. et al. Age-related macrophage alterations are associated with carcinogenesis of colorectal cancer. Carcinogenesis 43, 1039–1049 (2022).

    PubMed 
    CAS 

    Google Scholar 

  • Alicea, G. M. et al. Changes in aged fibroblast lipid metabolism induce age-dependent melanoma cell resistance to targeted therapy via the fatty acid transporter FATP2. Cancer Discov. 10, 1282–1295 (2020).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Hurez, V. et al. Mitigating age-related immune dysfunction heightens the efficacy of tumor immunotherapy in aged mice. Cancer Res. 72, 2089–2099 (2012).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Prieto, L. I. et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell 41, 1261–1275.e6 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Duan, R. et al. Aging-induced immune microenvironment remodeling fosters melanoma in male mice via γδ17-neutrophil-CD8 axis. Nat. Commun. 15, 10860 (2024). This study revealed that, in aged male mice, IL-17+ γδ T cells recruit neutrophils to the TME where they suppress CD8+ T cell effector function, resulting in enhanced melanoma, highlighting an age-associated and sex-associated immunosuppressive axis.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Kumar, S. et al. Uncovering therapeutic targets for macrophage-mediated T cell suppression and PD-L1 therapy sensitization. Cell Rep. Med. 5, 101698 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Coussens, L. M., Zitvogel, L. & Palucka, A. K. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339, 286–291 (2013).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Barry, S. T., Gabrilovich, D. I., Sansom, O. J., Campbell, A. D. & Morton, J. P. Therapeutic targeting of tumour myeloid cells. Nat. Rev. Cancer 23, 216–237 (2023).

    PubMed 
    CAS 

    Google Scholar 

  • Lue, J. C. & Radisky, D. C. From embryogenesis to senescence: the role of mammary gland physiology in breast cancer risk. Cancers 17, 787 (2025).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Khodr, Z. G. et al. Circulating sex hormones and terminal duct lobular unit involution of the normal breast. Cancer Epidemiol. Biomark. Prev. 23, 2765–2773 (2014).

    CAS 

    Google Scholar 

  • Zirbes, A. et al. Changes in immune cell types with age in breast are consistent with a decline in immune surveillance and increased immunosuppression. J. Mammary Gland. Biol. Neoplasia 26, 247–261 (2021). This study characterized age-related changes in immune cell composition and localization within normal human breast tissue, revealing a decline in peri-epithelial T cells and B cells and increased immunosuppressive macrophages with age, suggesting that age fosters immunosenescence and inflammation, increasing the susceptibility to breast cancer.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Shalabi, S. F. et al. Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations. Nat. Aging 1, 838–849 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Sayaman, R. W. et al. Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility. eLife 13, e95720 (2024).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Yan, P. et al. Midkine as a driver of age-related changes and increase in mammary tumorigenesis. Cancer Cell 42, 1936–1954.e9 (2024). This study identified a role for midkine in driving ageing-related changes in the mammary gland that associate with a reduction in TILs and promote breast cancer development.

    PubMed 
    CAS 

    Google Scholar 

  • Catena, X. et al. Systemic rewiring of dendritic cells by melanoma-secreted midkine impairs immune surveillance and response to immune checkpoint blockade. Nat. Cancer 6, 682–701 (2025).

    PubMed 
    CAS 

    Google Scholar 

  • Cerezo-Wallis, D. et al. Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state. Nat. Med. 26, 1865–1877 (2020).

    PubMed 
    CAS 

    Google Scholar 

  • Harper, E. I. & Weeraratna, A. T. A wrinkle in TIME: how changes in the aging ECM drive the remodeling of the tumor immune microenvironment. Cancer Discov. 13, 1973–1981 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Du, H. et al. Tuning immunity through tissue mechanotransduction. Nat. Rev. Immunol. 23, 174–188 (2023).

    PubMed 
    CAS 

    Google Scholar 

  • Kaur, A. et al. Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. Cancer Discov. 9, 64–81 (2019).

    PubMed 
    CAS 

    Google Scholar 

  • Marino, G. E. & Weeraratna, A. T. A glitch in the matrix: age-dependent changes in the extracellular matrix facilitate common sites of metastasis. Aging Cancer 1, 19–29 (2020).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Pettan-Brewer, C. et al. B16 melanoma tumor growth is delayed in mice in an age-dependent manner. Pathobiol. Aging Age Relat. Dis. 2, 19182 (2012).

    Google Scholar 

  • Reed, M. J. et al. The effects of aging on tumor growth and angiogenesis are tumor-cell dependent. Int. J. Cancer 120, 753–760 (2007).

    PubMed 
    CAS 

    Google Scholar 

  • Klement, H. et al. Atherosclerosis and vascular aging as modifiers of tumor progression, angiogenesis, and responsiveness to therapy. Am. J. Pathol. 171, 1342–1351 (2007).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Marinho, A., Soares, R., Ferro, J., Lacerda, M. & Schmitt, F. C. Angiogenesis in breast cancer is related to age but not to other prognostic parameters. Pathol. Res. Pract. 193, 267–273 (1997).

    PubMed 
    CAS 

    Google Scholar 

  • Khan, K. A. & Kerbel, R. S. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat. Rev. Clin. Oncol. 15, 310–324 (2018).

    PubMed 
    CAS 

    Google Scholar 

  • Donato, A. J., Morgan, R. G., Walker, A. E. & Lesniewski, L. A. Cellular and molecular biology of aging endothelial cells. J. Mol. Cell. Cardiol. 89, 122–135 (2015).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Liu, S. et al. ROS fine-tunes the function and fate of immune cells. Int. Immunopharmacol. 119, 110069 (2023).

    PubMed 
    CAS 

    Google Scholar 

  • Marino-Bravante, G. E. et al. Age-dependent loss of HAPLN1 erodes vascular integrity via indirect upregulation of endothelial ICAM1 in melanoma. Nat. Aging 4, 350–363 (2024).

    PubMed 
    CAS 

    Google Scholar 

  • Bui, T. M., Wiesolek, H. L. & Sumagin, R. ICAM-1: a master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis. J. Leukoc. Biol. 108, 787–799 (2020).

    PubMed 
    CAS 

    Google Scholar 

  • Upadhaya, S., Neftelinov, S. T., Hodge, J. & Campbell, J. Challenges and opportunities in the PD1/PDL1 inhibitor clinical trial landscape. Nat. Rev. Drug Discov. 21, 482–483 (2022).

    PubMed 
    CAS 

    Google Scholar 

  • Karin, O., Agrawal, A., Porat, Z., Krizhanovsky, V. & Alon, U. Senescent cell turnover slows with age providing an explanation for the Gompertz law. Nat. Commun. 10, 5495 (2019).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Coppé, J.-P., Desprez, P.-Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhou, L., Ma, B. & Ruscetti, M. Cellular senescence offers distinct immunological vulnerabilities in cancer. Trends Cancer 11, 334–350 (2024).

    PubMed 

    Google Scholar 

  • Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439–453 (2019).

    PubMed 
    CAS 

    Google Scholar 

  • Ruhland, M. K. et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 7, 11762 (2016).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Meguro, S. et al. Preexisting senescent fibroblasts in the aged bladder create a tumor-permissive niche through CXCL12 secretion. Nat. Aging 4, 1582–1597 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Assouline, B. et al. Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice. Nat. Commun. 15, 6162 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ye, J. et al. Senescent CAFs mediate immunosuppression and drive breast cancer progression. Cancer Discov. 14, 1302–1323 (2024). This study, together with Belle et al. (2024), identified a role for a population of senescent myofibroblastic CAFs in facilitating immune suppression in the TME by limiting NK cell-mediated anti-cancer immunity in a preclinical breast cancer model with parallel phenotypes in human cancer.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Belle, J. I. et al. Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer. Cancer Discov. 14, 1324–1355 (2024). 

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Pereira, B. I. et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat. Commun. 10, 2387 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Fane, M. & Weeraratna, A. T. How the ageing microenvironment influences tumour progression. Nat. Rev. Cancer 20, 89–106 (2020).

    PubMed 
    CAS 

    Google Scholar 

  • Ye, J., Melam, A. & Stewart, S. A. Stromal senescence contributes to age-related increases in cancer. Nat. Rev. Cancer (2025).

    PubMed 

    Google Scholar 

  • Kaur, A. et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532, 250–254 (2016).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Fane, M. E. et al. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature 606, 396–405 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zabransky, D. J. et al. Fibroblasts in the aged pancreas drive pancreatic cancer progression. Cancer Res. 84, 1221–1236 (2024). Using proteomics, the authors demonstrated that ageing alters pancreatic fibroblast secretomes, notably increasing GDF15 production, which promotes tumour progression via AKT activation in aged mice, revealing age-dependent microenvironmental mechanisms driving pancreatic cancer progression and potential therapeutic vulnerabilities.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ratnam, N. M. et al. NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development. J. Clin. Invest. 127, 3796–3809 (2017).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Carlson, E. G. et al. CD105+ fibroblasts support an immunosuppressive niche in women at high risk of breast cancer initiation. Breast Cancer Res. 27, 81 (2025).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ahmed, B. & Si, H. The aging of adipocytes increases expression of pro-inflammatory cytokines chronologically. Metabolites 11, 292 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Nguyen, T. T. & Corvera, S. Adipose tissue as a linchpin of organismal ageing. Nat. Metab. 6, 793–807 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Tanaka, T., Narazaki, M. & Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol. 6, a016295 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Yoshimura, T. et al. Non-myeloid cells are major contributors to innate immune responses via production of monocyte chemoattractant protein-1/CCL2. Front. Immunol. 4, 482 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, A. Y., Wolchok, J. D. & Bass, A. R. TNF in the era of immune checkpoint inhibitors: friend or foe? Nat. Rev. Rheumatol. 17, 213–223 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Gurung, S. et al. Stromal lipid species dictate melanoma metastasis and tropism. Cancer Cell 43, 1108–1124.e11 (2025).

    PubMed 
    CAS 

    Google Scholar 

  • Hubler, M. J. & Kennedy, A. J. Role of lipids in the metabolism and activation of immune cells. J. Nutr. Biochem. 34, 1–7 (2016).

    PubMed 
    CAS 

    Google Scholar 

  • Lazure, F. & Gomes, A. P. Cancer progression through the lens of age-induced metabolic reprogramming. Nat. Rev. Cancer (2025).

    PubMed 

    Google Scholar 

  • Yaniv, D., Mattson, B., Talbot, S., Gleber-Netto, F. O. & Amit, M. Targeting the peripheral neural-tumour microenvironment for cancer therapy. Nat. Rev. Drug Discov. 23, 780–796 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • White, C. W., Xie, J. H. & Ventura, S. Age-related changes in the innervation of the prostate gland: implications for prostate cancer initiation and progression. Organogenesis 9, 206–215 (2013).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Ayala, G. E. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 7593–7603 (2008).

    PubMed 
    CAS 

    Google Scholar 

  • Al-Danakh, A. et al. Aging-related biomarker discovery in the era of immune checkpoint inhibitors for cancer patients. Front. Immunol. 15, 1348189 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Voruganti, T., Soulos, P. R., Mamtani, R., Presley, C. J. & Gross, C. P. Association between age and survival trends in advanced non-small cell lung cancer after adoption of immunotherapy. JAMA Oncol. 9, 334–341 (2023).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Yin, J. et al. The efficacy of immune checkpoint inhibitors is limited in elderly NSCLC: a retrospective efficacy study and meta-analysis. Aging 15, 15025–15049 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ding, Y. et al. Age-related efficacy of immunotherapies in advanced non-small cell lung cancer: a comprehensive meta-analysis. Lung Cancer 195, 107925 (2024).

    PubMed 
    CAS 

    Google Scholar 

  • Ibrahim, T., Mateus, C., Baz, M. & Robert, C. Older melanoma patients aged 75 and above retain responsiveness to anti-PD1 therapy: results of a retrospective single-institution cohort study. Cancer Immunol. Immunother. 67, 1571–1578 (2018).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Li, P. et al. The impact of immunosenescence on the efficacy of immune checkpoint inhibitors in melanoma patients: a meta-analysis. Onco. Targets Ther. 11, 7521–7527 (2018).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Woo, T. E. et al. Effectiveness of immune checkpoint inhibitor with anti-PD-1 monotherapy or in combination with ipilimumab in younger versus older adults with advanced melanoma. Curr. Oncol. 30, 8936–8947 (2023).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim, C. M. et al. The efficacy of immune checkpoint inhibitors in elderly patients: a meta-analysis and meta-regression. ESMO Open 7, 100577 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Overman, M. J. et al. Nivolumab plus relatlimab in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J. Immunother. Cancer 12, e008689 (2024).

    PubMed 
    PubMed Central 

    Google Scholar 

  • André, T. et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N. Engl. J. Med. 383, 2207–2218 (2020).

    PubMed 

    Google Scholar 

  • Elias, R. et al. Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis. J. Immunother. Cancer 6, 26 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Nishijima, T. F., Muss, H. B., Shachar, S. S. & Moschos, S. J. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat. Rev. 45, 30–37 (2016).

    PubMed 
    CAS 

    Google Scholar 

  • Cil, E. & Gomes, F. Toxicity of cancer immunotherapies in older patients: does age make a difference? Drugs Aging 41, 787–794 (2024).

    PubMed 

    Google Scholar 

  • Cook, S. L. et al. Immune checkpoint inhibitors in geriatric oncology. Curr. Oncol. Rep. 26, 562–572 (2024).

    PubMed 

    Google Scholar 

  • Spigel, D. R. et al. Safety, efficacy, and patient-reported health-related quality of life and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged 70 years or older or with poor performance status (CheckMate 153). J. Thorac. Oncol. 14, 1628–1639 (2019).

    PubMed 
    CAS 

    Google Scholar 

  • Felip, E. et al. CheckMate 171: a phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations. Eur. J. Cancer 127, 160–172 (2020).

    PubMed 
    CAS 

    Google Scholar 

  • US National Library of Medicine. Clinicaltrials.gov (2019).

  • US National Library of Medicine. Clinicaltrials.gov (2023).

  • US National Library of Medicine. Clinicaltrials.gov (2024).

  • US National Library of Medicine. Clinicaltrials.gov (2023).

  • US National Library of Medicine. Clinicaltrials.gov (2018).

  • US National Library of Medicine. Clinicaltrials.gov (2023).

  • US National Library of Medicine. Clinicaltrials.gov (2024).

  • US National Library of Medicine. Clinicaltrials.gov (2023).

  • Johnson, D. B., Sullivan, R. J. & Menzies, A. M. Immune checkpoint inhibitors in challenging populations. Cancer 123, 1904–1911 (2017).

    PubMed 

    Google Scholar 

  • Blanco, R. et al. Pembrolizumab as first-line treatment for advanced NSCLC in older adults: a phase II clinical trial evaluating geriatric and quality-of-life outcomes. Lung Cancer 183, 107318 (2023).

    PubMed 
    CAS 

    Google Scholar 

  • Tran Van Hoi, E. et al. Blood based immune biomarkers associated with clinical frailty scale in older patients with melanoma receiving checkpoint inhibitor immunotherapy. Immun. Ageing 21, 83 (2024). This is the first prospective clinical trial to use both frailty assessment and immunophenotyping to determine whether advanced age and frailty correlate with baseline immune health and responses to anti-PD1-checkpoint blockade therapy.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Bruijnen, C. P. et al. Frailty and checkpoint inhibitor toxicity in older patients with melanoma. Cancer 128, 2746–2752 (2022).

    PubMed 

    Google Scholar 

  • La, J. et al. Real-world outcomes for patients treated with immune checkpoint inhibitors in the Veterans Affairs system. JCO Clin. Cancer Inform. 4, 918–928 (2020).

    PubMed 

    Google Scholar 

  • US National Library of Medicine. Clinicaltrials.gov (2017).

  • US National Library of Medicine. Clinicaltrials.gov (2020).

  • Reitsema, R. D., Kumawat, A. K., Hesselink, B.-C., van Baarle, D. & van Sleen, Y. Effects of ageing and frailty on circulating monocyte and dendritic cell subsets. NPJ Aging 10, 17 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Samson, L. D. et al. In-depth immune cellular profiling reveals sex-specific associations with frailty. Immun. Ageing 17, 20 (2020).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Sayed, N. et al. An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nat. Aging 1, 598–615 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Nakajima, Y., Chamoto, K., Oura, T. & Honjo, T. Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice. Proc. Natl Acad. Sci. USA 118, e2103730118 (2021).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Padrón, Á. et al. Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model. Exp. Gerontol. 105, 146–154 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Garcia, M. G. et al. Immune checkpoint expression and relationships to anti-PD-L1 immune checkpoint blockade cancer immunotherapy efficacy in aged versus young mice. Aging Cancer 3, 68–83 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Sekido, K. et al. Alterations in composition of immune cells and impairment of anti-tumor immune response in aged oral cancer-bearing mice. Oral. Oncol. 99, 104462 (2019).

    PubMed 
    CAS 

    Google Scholar 

  • Ladomersky, E. et al. Advanced age increases immunosuppression in the brain and decreases immunotherapeutic efficacy in subjects with glioblastoma. Clin. Cancer Res. 26, 5232–5245 (2020).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Mo, D.-C. et al. The role of PD-L1 in patients with non-small cell lung cancer receiving neoadjuvant immune checkpoint inhibitor plus chemotherapy: a meta-analysis. Sci. Rep. 14, 26200 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Cortes, J. et al. Contribution of tumour and immune cells to PD-L1 expression as a predictive biomarker in metastatic triple-negative breast cancer: exploratory analysis from KEYNOTE-119. J. Pathol. Clin. Res. 10, e12371 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Schoenfeld, A. J. et al. Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas. Ann. Oncol. 31, 599–608 (2020).

    PubMed 
    CAS 

    Google Scholar 

  • Mirza, N. et al. B7-H1 expression on old CD8+ T cells negatively regulates the activation of immune responses in aged animals. J. Immunol. 184, 5466–5474 (2010). This was the first preclinical study to assess the efficacy of PDL1-checkpoint blockade in aged versus young adult mice; they found that aged mice upregulate PDL1, rendering checkpoint blockade highly effective.

    PubMed 
    CAS 

    Google Scholar 

  • Sun, X. et al. Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets. J. Clin. Invest. 132, e158122 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ladomersky, E. et al. Advanced age negatively impacts survival in an experimental brain tumor model. Neurosci. Lett. 630, 203–208 (2016).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Gardner, J. K., Jackaman, C., Mamotte, C. D. S. & Nelson, D. J. The regulatory status adopted by lymph node dendritic cells and T cells during healthy aging is maintained during cancer and may contribute to reduced responses to immunotherapy. Front. Med. 5, 337 (2018).

    Google Scholar 

  • Freedman, R. A. et al. “ADVANCE” (a pilot trial) ADjuVANt chemotherapy in the elderly: developing and evaluating lower-toxicity chemotherapy options for older patients with breast cancer. J. Geriatr. Oncol. 14, 101377 (2023). This pragmatic pilot trial evaluated the feasibility of two neoadjuvant or adjuvant chemotherapy regimens in adults over 70 years of age with HER2-negative breast cancer and found that neither regimen met pre-defined feasibility thresholds, underscoring the need for more tolerable, age-adapted therapeutic strategies for older patients, who are underrepresented in clinical trials.

    PubMed 
    CAS 

    Google Scholar 

  • Piccart, M. et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol. 22, 476–488 (2021).

    PubMed 
    CAS 

    Google Scholar 

  • Guida, J. L., Gallicchio, L. & Green, P. A. Are early-onset cancers an example of accelerated biological aging? JAMA Oncol. 11, 690–691 (2025).

    PubMed 

    Google Scholar 

  • Castaño, Z., Tracy, K. & McAllister, S. S. The tumor macroenvironment and systemic regulation of breast cancer progression. Int. J. Dev. Biol. 55, 889–897 (2011).

    PubMed 

    Google Scholar 

  • Duan, R., Fu, Q., Sun, Y. & Li, Q. Epigenetic clock: a promising biomarker and practical tool in aging. Ageing Res. Rev. 81, 101743 (2022).

    PubMed 
    CAS 

    Google Scholar 

  • Yamamoto, R. et al. Tissue-specific impacts of aging and genetics on gene expression patterns in humans. Nat. Commun. 13, 5803 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Slieker, R. C., Relton, C. L., Gaunt, T. R., Slagboom, P. E. & Heijmans, B. T. Age-related DNA methylation changes are tissue-specific with ELOVL2 promoter methylation as exception. Epigenetics Chromatin 11, 25 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Dugué, P.-A. et al. Biological aging measures based on blood DNA methylation and risk of cancer: a prospective study. JNCI Cancer Spectr. 5, kaa109 (2021).

    Google Scholar 

  • Tserel, L. et al. Age-related profiling of DNA methylation in CD8+ T cells reveals changes in immune response and transcriptional regulator genes. Sci. Rep. 5, 13107 (2015).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Tsukamoto, H. et al. Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events. Proc. Natl Acad. Sci. USA 119, e2205378119 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Weyh, C., Krüger, K. & Strasser, B. Physical activity and diet shape the immune system during aging. Nutrients 12, 622 (2020).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Bachmann, M. C. et al. The challenge by multiple environmental and biological factors induce inflammation in aging: their role in the promotion of chronic disease. Front. Immunol. 11, 570083 (2020).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Besedovsky, L., Lange, T. & Born, J. Sleep and immune function. Pflug. Arch. 463, 121–137 (2012).

    CAS 

    Google Scholar 

  • Dhabhar, F. S. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol. Res. 58, 193–210 (2014).

    PubMed 
    CAS 

    Google Scholar 

  • Walford, R. L. The immunologic theory of aging. Gerontologist 4, 195–197 (1964).

    PubMed 
    CAS 

    Google Scholar 

  • Henson, S. M. et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J. Clin. Invest. 124, 4004–4016 (2014).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Simon, S. & Labarriere, N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology 7, e1364828 (2017).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Jenkins, E., Whitehead, T., Fellermeyer, M., Davis, S. J. & Sharma, S. The current state and future of T-cell exhaustion research. Oxf. Open Immunol. 4, iqad006 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Akbar, A. N. & Henson, S. M. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289–295 (2011).

    PubMed 
    CAS 

    Google Scholar 

  • Yang, Y., Li, T. & Nielsen, M. E. Aging and cancer mortality: dynamics of change and sex differences. Exp. Gerontol. 47, 695–705 (2012).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Bonafè, M. et al. Inflamm-aging: why older men are the most susceptible to SARS-CoV-2 complicated outcomes. Cytokine Growth Factor Rev. 53, 33–37 (2020).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Sefik, E. et al. Inflammasome activation in infected macrophages drives COVID-19 pathology. Nature 606, 585–593 (2022).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ravichandran, S. et al. Distinct baseline immune characteristics associated with responses to conjugated and unconjugated pneumococcal polysaccharide vaccines in older adults. Nat. Immunol. 25, 316–329 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Pido-Lopez, J., Imami, N. & Aspinall, R. Both age and gender affect thymic output: more recent thymic migrants in females than males as they age. Clin. Exp. Immunol. 125, 409–413 (2001).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Castro, A. et al. Strength of immune selection in tumors varies with sex and age. Nat. Commun. 11, 4128 (2020). This study demonstrated that the strength of MHC-mediated immune selection during tumorigenesis varies by age and sex, with younger and female patients experiencing poorer response rates to ICI therapy than those of older and male patients due to reduced neoantigen availability.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Xiao, T. et al. Hallmarks of sex bias in immuno-oncology: mechanisms and therapeutic implications. Nat. Rev. Cancer 24, 338–355 (2024).

    PubMed 
    CAS 

    Google Scholar 

  • Thompson, D. J. et al. Genetic predisposition to mosaic Y chromosome loss in blood. Nature 575, 652–657 (2019).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Grigoryan, A. et al. Attrition of X chromosome inactivation in aged hematopoietic stem cells. Stem Cell Rep. 16, 708–716 (2021).

    CAS 

    Google Scholar 

  • Forsberg, L. A. et al. Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat. Genet. 46, 624–628 (2014).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Chhabra, Y. et al. Sex-dependent effects in the aged melanoma tumor microenvironment influence invasion and resistance to targeted therapy. Cell 187, 6016–6034.e25 (2024).

    PubMed 
    CAS 

    Google Scholar 

  • Warde, K. M. et al. Senescence-induced immune remodeling facilitates metastatic adrenal cancer in a sex-dimorphic manner. Nat. Aging 3, 846–865 (2023).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

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