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Protein Phosphatase 2A (PP2A) complexes counteract diverse kinase-driven oncogenic pathways. Accumulating clinical evidence further underscores impaired PP2A function/activity in diverse cancers, sustaining its suspected tumor suppressor function. Nevertheless, whether loss of PP2A activity is sufficient for tumorigenesis in vivo has remained elusive. Here, we describe development of spontaneous malignancies in mice (haplo)deficient for Ppp2r4, encoding a PP2A chaperone (PTPA) essential for generation of active PP2A holoenzymes. PTPA-deficient tissues show reduced PP2A activity and methylation, selectively affecting specific PP2A holoenzymes. Complementary analyses of protein phosphorylation and gene expression revealed heterogeneous activation of diverse oncogenic signaling pathways in the tumors, underscoring that decreased PP2A activity affects multiple targets. Importantly, cancer database surveys revealed heterozygous PPP2R4 deletion at strikingly high frequency in several human cancer types. Furthermore, cancer-derived PPP2R4 mutants showing impaired PP2A-C binding in cellulo or impaired PTPA activity in vitro were unable to rescue transformation of PTPA-depleted human HEK-TER cells. Our data provide the first compelling in vivo evidence that impaired PP2A activity is sufficient to promote tumor development and establish PPP2R4 as a novel haploinsufficient tumor suppressor gene in multiple human cancers. These findings ultimately validate PP2A as a bona fide tumor suppressor and target for tumor suppressor reactivation therapies.