PPP2R1A encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a master regulator of cellular signaling, genome stability, and immune homeostasis. Although PPP2R1A mutations have been associated with aggressive tumor behavior, particularly in gynecologic malignancies, emerging clinical evidence reveals a paradoxical association with enhanced sensitivity to cancer immunotherapy. Tumors harboring PPP2R1A mutations exhibit heightened IFN-γ signaling, increased CD8⁺ T-cell infiltration, and organized immune microstructures, correlating with exceptional responses to immune checkpoint blockade (ICB). In this Perspective, we synthesize recent mechanistic and translational studies to explain how distinct forms of PPP2R1A perturbation, including genetic knockout, knockdown, cancer-associated PPP2R1A mutations, and pharmacologic PP2A inhibition, produce fundamentally different biochemical consequences for PP2A holoenzyme assembly and activity. We discuss how PPP2R1A loss can induce mismatch repair deficiency, activate cGAS–STING signaling, disrupt regulatory T-cell function, and promote neoantigen generation, collectively converting immunologically “cold” tumors into “hot” ones. We further explore the clinical implications of these findings, including encouraging results from early-phase trials combining PP2A inhibitors (e.g., LB-100) with ICB across multiple tumor types. By integrating mechanistic insight with translational relevance, this Perspective article underscores the potential of PPP2R1A -guided immunotherapy and outlines rational combination strategies that target PP2A biology to enhance antitumor immunity.
Canhui Cao (Sun,) studied this question.