Abstract
Aneuploidy, a hallmark of cancer characterized by chromosome imbalances, drives tumorigenesis and facilitates cancer immune evasion. While high tumor aneuploidy is linked to immune checkpoint blockade (ICB) resistance and poor prognosis, evidence suggests that this resistance can be overcome through treatment intensification, for example, with the addition of ablative radiotherapy to ICB. In this Perspective, we argue that the predictive value of aneuploidy complements established biomarkers, such as tumor mutational burden (TMB) or programmed death ligand 1 (PD-L1) expression. We review contemporary methods for quantifying aneuploidy, explore novel approaches that target mitotic vulnerabilities in aneuploid tumors and highlight potential areas where aneuploidy-based stratification could be incorporated into ICB-based treatment paradigms across early-stage, locally advanced and metastatic cancers. Prospective trials incorporating aneuploidy-based stratification will be essential to validate its role in personalized cancer therapy.
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Acknowledgements
S.P.P. is supported by the LUNGevity Foundation, the Falk Medical Research Trust and the American Lung Association. S.P.P. and R.R.W. receive funding from the National Institutes of Health (U54-CA274291 ROBIN grant) and the Ludwig Cancer Research Foundation.
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D.H. wrote the initial draft of the manuscript and designed the figure with input from all authors. L.F.S. contributed his technical expertise on the quantification of tumor aneuploidy. D.H., L.F.S., R.R.W. and S.P.P. provided critical revisions to the manuscript.
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R.R.W. has stock and other ownership interests with Boost Therapeutics, ImmVira, RefleXion Pharmaceuticals, Coordination Pharmaceuticals, Magi Therapeutics and Oncosenescence. He has served in a consulting or advisory role for Aettis, AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono, Nanoproteagen, NKMax America and Shuttle Pharmaceuticals. He has received research grant funding from Varian and Regeneron. He has received compensation including travel, accommodations or expense reimbursement from AstraZeneca, Boehringer Ingelheim and Merck Serono. S.P.P. and R.R.W. own a patent related to this work (PCT/US23/81165). S.P.P. and R.R.W. are cofounders of PersonaDx. The other authors declare no competing interests.
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Huang, D., Spurr, L.F., Weichselbaum, R.R. et al. Tumor aneuploidy as a prognostic and predictive biomarker in immune checkpoint blockade. Nat Genet 57, 1802–1811 (2025). https://doi.org/10.1038/s41588-025-02226-x
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DOI: https://doi.org/10.1038/s41588-025-02226-x
