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Stemness in solid malignancies: coping with immune attack

Nature Reviews Cancer volume 25, pages 27–40 (2025)Cite this article

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Abstract

Immunotherapy has become a key new pillar of cancer treatment, and this has sparked interest in understanding mechanisms of cancer immune evasion. It has long been appreciated that cancers are constituted by heterogeneous populations of tumour cells. This feature is often fuelled by specialized cells that have molecular programs resembling tissue stem cells. Although these cancer stem cells (CSCs) have capacity for unlimited self-renewal and differentiation, it is increasingly evident that some CSCs are capable of achieving remarkable immune resistance. Given that most immunotherapy regiments have overlooked CSC-specific immune-evasive mechanisms, many current treatment strategies often lead to cancer relapse. This Review focuses on advancements in understanding how CSCs in solid tumours achieve their unique immune-evasive properties, enabling them to drive tumour regrowth. Moreover, as cancers often arise from tissue stem cells that acquired oncogenic mutations, we discuss how tissue stem cells undergoing malignant transformation activate intrinsic immune-evasive mechanisms and establish close interactions with suppressive immune cells to escape immune surveillance. In addition, we summarize how in advanced disease stages, CSCs often hijack features of normal stem cells to resist antitumour immunity. Finally, we provide insights in how to design a new generation of cancer immunotherapies to ensure elimination of CSCs.

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Fig. 1: Response of healthy adult tissue resident stem cells to immune attack and inflammation.
Fig. 2: Cytotoxic-mediated immune surveillance of tumour-initiating stem cells.
Fig. 3: CSCs exploit a combination of cell-intrinsic and cell-extrinsic mechanisms to evade T cell immunity.

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Acknowledgements

We thank grant supports from the US National Institutes of Health (R01CA285786 to Y.M.). J.A. is supported by R01DK132544, the Ludwig Center at Harvard, the Innovation research Funds at Dana-Farber Cancer Institute, the Parker Institute for Cancer Immunotherapy, the Department of Defense-Breast Cancer Program and the New York Stem Cell Foundation — Robertson Investigator.

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Author notes

  1. These authors contributed equally: Judith Agudo, Yuxuan Miao.

Authors and Affiliations

  1. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA

    Judith Agudo

  2. Department of Immunology, Harvard Medical School, Boston, MA, USA

    Judith Agudo

  3. Ludwig Center at Harvard, Boston, MA, USA

    Judith Agudo

  4. Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA, USA

    Judith Agudo

  5. New York Stem Cell Foundation, Robertson Investigator, New York, NY, USA

    Judith Agudo

  6. Ben May Department of Cancer Research, The University of Chicago, Chicago, IL, USA

    Yuxuan Miao

  7. The University of Chicago Comprehensive Cancer Center, Chicago, IL, USA

    Yuxuan Miao

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  1. Judith Agudo
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  2. Yuxuan Miao
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The authors contributed equally to all aspects of the article.

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Nature Reviews Cancer thanks Justin Lathia, Andreas Trumpp, who co-reviewed with Jennifer Wischhusen and Patrick Stelmach, Linheng Li, who co-reviewed with Lu Deng, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Allograft transplant

Transplant tissues or organs from a genetically non-identical donor of the same species.

Autochthonous tumours

Animal models for human cancers that are generated by initiating tumours in a normal cell of a mouse.

Cytotoxic innate-like T cells

Unconventional cytotoxic T cells that express T cell receptors that do not recognize MHC–peptide complexes.

Exhausted T cells

A T cell state in which they lose the ability to quickly proliferate, produce cytokines and kill the target cells.

Innate immune sensors

An evolutionarily conserved system that senses the molecular patterns associated with pathogen or danger signals to provide the first line of defence.

Label-retaining cells

An approach that can identify stem and progenitor cells by their quiescent nature, so that the slow-cycling stem cells will retain the labelling for longer periods of time.

Limiting dilution transplantation assays

Assays in which transplantation of increasingly diluted single-cell suspensions of cells into recipient animals enables the estimation of their self-renewal and differentiation potential.

Major histocompatibility complex class I

The molecules found on the surface of all nucleated cells to display peptides from intracellular proteins (namely, antigens) to CD8+ T cells.

Metastasis-initiating cells

A special group of stem-like cancer cells that can initiate and sustain metastasis in a new organ.

Stem cell plasticity

The ability of stem cells to alter their epigenetic landscape and transcriptome profile to acquire a different cell state or cell identity.

Stemness

The cellular potential to achieve long-term self-renewal and multilineage differentiation.

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Agudo, J., Miao, Y. Stemness in solid malignancies: coping with immune attack. Nat Rev Cancer 25, 27–40 (2025). https://doi.org/10.1038/s41568-024-00760-0

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