UFSP2 constitutes a targetable vulnerability via deUFMylation-dependent activation of AKT oncogenic signaling

AKT hyperactivation is a hallmark of many human cancers and contributes to poor clinical outcomes, yet the underlying mechanisms remain incompletely understood. Here, we show that AKT undergoes UFMylation, and loss of AKT UFMylation promotes colorectal tumor development and confers resistance to the AKT inhibitor AZD5363 (capivasertib). Furthermore, p53 activates ubiquitin-fold modifier 1 (UFM1) during the cell cycle to inhibit AKT activity. Conversely, AKT phosphorylates UFM1 to reduce its own UFMylation, establishing a feedback loop that sustains AKT activity. Moreover, we provide evidence that UFSP2 functions as a major cellular deUFMylase for AKT, and genetic ablation or inhibition of UFSP2 suppresses AKT activity to retard tumorigenesis in vivo. Together, these findings provide a mechanistic framework for UFMylation-dependent AKT regulation and support further investigation of UFSP2 inhibition as a potential strategy to modulate AKT signaling in colorectal cancer.