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

UFSP2 is a major deUFMylase for AKT, and UFSP2 genetic ablation or inhibition suppresses AKT activity, retarding colorectal tumorigenesis in vivo.

• Why it matters: AKT hyperactivation is linked to poor outcomes in many cancers, but the UFMylation-dependent mechanisms controlling AKT activity and therapeutic vulnerability are not fully defined.
• What they did: The study shows AKT undergoes UFMylation; loss of AKT UFMylation promotes colorectal tumor development and confers resistance to AZD5363 (capivasertib), while p53 and AKT form a UFM1–AKT feedback loop.
• The result: UFSP2 inhibition suppresses AKT activity and retards tumorigenesis in vivo, supporting UFSP2 as a targetable vulnerability to modulate AKT signaling in colorectal cancer.