The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Dai, Y., Knisely, A., Yano, M., Dang, M. et al. Nature. 644: 537–546. (2025).
doi: 10.1038/s41586-025-09203-8.
Summary of the findings
Immune checkpoint blockade (ICB) has limited efficacy in ovarian cancer, where predictive biomarkers are lacking. However, about 5-15% of patients respond and are often over-represented in the clear cell histological subtype. In this study, we identified several lines of evidence pointing to loss-of-function somatic mutations in PPP2R1A, a scaffold subunit of the phosphatase 2 A (PP2A) complex, as a predictor of improved outcomes with ICB. Among patients with platinum-resistant ovarian clear cell carcinomas (OCCC), PPP2R1A-mutated tumors were associated with significantly prolonged overall and progression-free survival compared to wild-type cases. Validation across independent ICB-treated cohorts from multiple cancer types confirmed this association. Mechanistic analyses demonstrated that PPP2R1A mutations enhanced IFNγ signaling, increased immune infiltration, and promoted expansion of CD45RO⁺CD8⁺ T cells, with evidence of tertiary lymphoid structures. Preclinical models further showed that genetic or pharmacologic inhibition of PPP2R1A sensitized tumors to ICB and CAR-T therapies. Collectively, these findings suggest that PPP2R1A mutations represent a predictive biomarker of ICB response and a potential therapeutic target. Further studies are ongoing to clarify mechanisms and evaluate PP2A inhibition as a strategy to broaden immunotherapy benefit.
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Future Impact
If validated, our findings establish PPP2R1A mutations leasing to PP2A inhibition as a predictive biomarker for immune checkpoint blockade responsiveness, with potential relevance across multiple tumor types. Beyond biomarker development, pharmacologic inhibition of PP2A may replicate the immunologic advantages of PPP2R1A loss, offering a strategy to sensitize otherwise resistant tumors to immunotherapy. Integration of PPP2R1A testing into clinical trials could guide patient selection, while PP2A-targeted therapies may expand treatment options. Together, these approaches could transform immunotherapy for ovarian clear cell carcinoma and other malignancies, improving durability and breadth of clinical benefit.
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