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Probing the physical hallmarks of cancer

Nature Methods volume 22, pages 1800–1818 (2025)Cite this article

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Abstract

The physical microenvironment plays a crucial role in tumor development, progression, metastasis and treatment. Recently, we proposed four physical hallmarks of cancer, with distinct origins and consequences, to characterize abnormalities in the physical tumor microenvironment: (1) elevated compressive–tensile solid stresses, (2) elevated interstitial fluid pressure and the resulting interstitial fluid flow, (3) altered material properties (for example, increased tissue stiffness) and (4) altered physical micro-architecture. As this emerging field of physical oncology is being advanced by tumor biologists, cell and developmental biologists, engineers, physicists and oncologists, there is a critical need for model systems and measurement tools to mechanistically probe these physical hallmarks. Here, after briefly defining these physical hallmarks, we discuss the tools and model systems available for probing each hallmark in vitro, ex vivo, in vivo and in clinical settings. We finally review the unmet needs for mechanistic probing of the physical hallmarks of tumors and discuss the challenges and unanswered questions associated with each hallmark.

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Fig. 1: Solid stress, range of values, measurement tools and experimental model systems.
Fig. 2: IFP and interstitial fluid flow, range of values, measurement tools and experimental model systems.
Fig. 3: Stiffness (rigidity), range of values, measurement tools and experimental model systems.
Fig. 4: Architecture and geometry: representative observations and experimental model systems.

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Acknowledgements

This work was supported in part by the National Cancer Institute (R01-CA259253, R01-CA208205, R01-NS118929, U01-CA261842, U01-CA 224348), an Outstanding Investigator Award (R35-CA197743 to R.K.J.), R01-CA204949 and R01-HL128168 to L.L.M. and R21EB031332, DP2HL168562, a Beckman Young Investigator Award, an NSF CAREER Award, a Kilachand Fund Award, a Sloan Research Fellowship and DoD HT9425241053 to H.T.N. R.K.J.’s research is also supported by grants from the National Foundation for Cancer Research, the Nile Albright Research Foundation, the Harvard Ludwig Center, Jane’s Trust Foundation and the Bill and Melinda Gates Foundation and Boehringer Ingelheim and Sanofi.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Boston University, Boston, MA, USA

    Hadi T. Nia

  2. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Lance L. Munn & Rakesh K. Jain

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  1. Hadi T. Nia
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  2. Lance L. Munn
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Contributions

H.T.N., L.L.M. and R.K.J. conceived and jointly wrote the Review.

Corresponding authors

Correspondence to Hadi T. Nia, Lance L. Munn or Rakesh K. Jain.

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Competing interests

R.K.J. received consultant and/or SAB fees from Cur, DynamiCure, Elpis, Merck and SynDevRx; owns equity in Accurius, Enlight and SynDevRx; and served on the boards of trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. The Massachusetts General Hospital has applied for patents related to concepts discussed in this Review. L.L.M. receives equity from Bayer and is a consultant for SimBioSys. The remaining author declares no competing interests.

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Nature Methods thanks Konstantinos Konstantopoulos and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Madhura Mukhopadhyay, in collaboration with the Nature Methods team.

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Nia, H.T., Munn, L.L. & Jain, R.K. Probing the physical hallmarks of cancer. Nat Methods 22, 1800–1818 (2025). https://doi.org/10.1038/s41592-024-02564-4

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