Targeting PP2A in cancer: an underrated option.

Protein phosphatase 2A plays a central role in modulating multiple signaling pathways, including PI3K, EGFR, Myc, WNT, JAK/STAT, RAS/MAPK, and NF-κB, which are frequently dysregulated in cancer. Although PP2A is broadly considered a tumor suppressor due to its frequent functional loss in tumors, its biological role is highly context-dependent and varies across cancer types and stages. The activity of the heterotrimeric PP2A complex is tightly controlled by the precise assembly and composition of the scaffolding (A), catalytic (C), and variable regulatory (B) subunits, with the latter exhibiting tissue- and developmental stage-specific patterns, thus allowing PP2A to exert context-dependent effects on signaling networks. In many cancers, PP2A dysregulation arises from mutations in subunit genes, post-translational modifications, or disrupted expression, leading to impaired holoenzyme formation and loss of activity. PP2A dysfunctionality often promotes the aberrant activation of pathways, including mTOR, and the enhanced phosphorylation of own and downstream targets, such as S6 kinase, facilitating tumor growth and progression. In this review, we discuss the mechanisms of PP2A dysregulation in cancer and highlight PP2A restoration as a promising therapeutic approach.