The role of PPP2R1A variants in gynecologic malignancies: a paradigm shift in immuno-oncology

BACKGROUND: Protein Phosphatase 2 A (PP2A), a key tumor suppressor, is frequently inactivated in cancer through mutations in its scaffold-encoding gene, PPP2R1A. This is particularly common in aggressive gynecologic malignancies, specifically uterine serous carcinoma (USC) and ovarian clear cell carcinoma (OCCC). A compelling paradox has emerged: while these mutations are potent oncogenic drivers, they are also powerful predictive biomarkers for an exceptional response to immune checkpoint inhibitor (ICI) therapy. MAIN BODY: This study provides a comprehensive narrative review of the literature to dissect the dual role of PPP2R1A in gynecologic cancers. This review elucidates the molecular pathogenesis and immune activation mechanisms of PPP2R1A mutations, while also outlining emerging therapeutic strategies targeting this pathway. CONCLUSIONS: The dual function of PPP2R1A mutations represents a paradigm shift in the field. Understanding this pathway provides crucial new insights that are poised to advance the future of precision immuno-oncology for patients with gynecologic cancers.