PPP2R2A encodes the B55α regulatory subunit of protein phosphatase 2A (PP2A), a serine/threonine phosphatase that controls cell cycle progression by mediating dephosphorylation of key checkpoint proteins. The protein is essential for regulating mitosis entry and exit, particularly through PP2A-dependent dephosphorylation of WEE1, which prevents its degradation and sustains the G2/M checkpoint. Beyond cell cycle control, PPP2R2A regulates mitochondrial homeostasis by coordinating mitophagy and biogenesis, with PP2A-B55α controlling both early events (ULK1 release) and late execution (TFEB nuclear translocation) of mitochondrial degradation pathways. In cancer, PPP2R2A loss of heterozygosity occurs in greater than 40% of non-small cell lung cancer cases and is associated with poor prognosis. Mechanistically, PPP2R2A deficiency enhances replication stress and promotes epithelial-mesenchymal transition via GSK3β-β-catenin signaling. This creates distinct therapeutic opportunities: in lung cancer, PPP2R2A-deficient tumors show enhanced sensitivity to PD-L1 checkpoint blockade through cGAS-STING pathway activation, with anti-PD-L1 antibodies demonstrating superior efficacy 1. In ovarian cancer, PPP2R2A deficiency increases c-Myc-driven replication stress, rendering cells reliant on CHK1 for survival and potentially responsive to CHK1 inhibitors 2. Additionally, PPP2R2A alterations were identified as a component of a predictive biomarker signature in metastatic castration-resistant prostate cancer treated with olaparib 3. Recent work identifies PP2A-B55α as a master regulator of mitochondrial dynamics with potential applications in neurodegenerative disease 4.