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  • Perspective
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Restoring resident tissue macrophages to combat aging and cancer

Nature Aging volume 5, pages 1383–1392 (2025)Cite this article

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Abstract

Perturbations to the immune system influence organismal aging, yet identifying effective therapeutic targets that mitigate aging-related tissue decline or the pathogenesis of aging-related diseases, such as cancer, remains challenging. In this Perspective, we focus on the dysfunction and loss of resident tissue macrophages (RTMs) with aging of certain tissues, which promote local inflammation, compromise tissue health and contribute to tumorigenesis. The abnormal genesis of RTMs from the bone marrow is a defining hallmark of both healthy and unhealthy aging. So, we propose that restoring RTMs—either by reshaping their niche and rescuing local self-renewal or by rejuvenating aging-associated myelopoiesis in the bone marrow—should be a major objective of interventions to promote healthy aging. We summarize the body of work supporting this conceptual framework and outline key future directions for the development of versatile myeloid-targeting therapies.

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Fig. 1: Dysregulation of RTMs as the myeloid basis for aging and cancer.
Fig. 2: Strategies for targeting myeloid pathways for antiaging and anticancer therapy.

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Author notes

  1. These authors contributed equally: Nader Yatim, Jing Zhang, Byuri Angela Cho, Seong-Keun Yoo, Maximilian M. Schaefer.

Authors and Affiliations

  1. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Matthew D. Park, Nader Yatim, Jing Zhang, Byuri Angela Cho, Seong-Keun Yoo, Maximilian M. Schaefer, Diego Chowell, Daniel J. Puleston & Miriam Merad

  2. Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Matthew D. Park, Nader Yatim, Jing Zhang, Byuri Angela Cho, Seong-Keun Yoo, Maximilian M. Schaefer, Diego Chowell, Daniel J. Puleston & Miriam Merad

  3. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Matthew D. Park, Nader Yatim, Jing Zhang, Byuri Angela Cho, Seong-Keun Yoo, Maximilian M. Schaefer, Diego Chowell, Daniel J. Puleston & Miriam Merad

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Contributions

Conceptualization: M.M. and M.D.P.; writing—original draft: M.D.P.; writing—reviewing and editing: M.M., D.J.P., D.C., N.Y. and J.Z.; assessment of literature: B.A.C., S.-K.Y. and M.M.S.

Corresponding author

Correspondence to Miriam Merad.

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Competing interests

M.M. serves on the scientific advisory board of and holds stock from Compugen Inc., Dynavax Inc., Asher Bio Inc., Dren Bio Inc., Genenta Inc., Oncoresponse Inc., Myeloid Therapeutics Inc., DemBio Inc. and Owkin Inc. M.M. serves on the scientific advisory board for contracted research from Genentech Inc., Regeneron Inc. and Boehringer Ingelheim Inc. M.M. is listed as an inventor on a patent application (#16/092576) submitted by the Icahn School of Medicine at Mount Sinai that covers the use of multiplex immunohistochemistry to characterize tumors and treatment responses. The technology is filed through the Icahn School of Medicine at Mount Sinai and is currently unlicensed. The other authors declare no competing interests.

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Nature Aging thanks Juan Pedro Martínez-Barbera, Irving Weissman and Yushi Yao for their contribution to the peer review of this work.

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Park, M.D., Yatim, N., Zhang, J. et al. Restoring resident tissue macrophages to combat aging and cancer. Nat Aging 5, 1383–1392 (2025). https://doi.org/10.1038/s43587-025-00898-y

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