Senescent CD9+Dll4+ neutrophils induced tumoral F1,6P allosterically recovers AKT kinase for rapid adaption of Capivasertib

Protein kinase B (PKB), also known as AKT, is essential for various cellular functions and is frequently hyperactivated in cancers, leading to decreased survival and poor prognoses. Capivasertib, an ATP-competitive AKT inhibitor, directly binds the ATP-binding pocket of AKT and blocks its phosphorylation and activation, thus impeding downstream signaling that promotes cell cycle progression and survival. However, the resistance to capivasertib remains unclear. Here, we show that CD9+ senescent neutrophils activate the Notch pathway in tumours via Delta-like ligand 4 (DLL4), leading to upregulation of PFKPL and increased levels of the metabolite fructose-1,6-bisphosphate (F1,6BP). F1,6BP then modulates the interaction between capivasertib and AKT through an allosteric effect, facilitating rapid adaptation to capivasertib. This study underscores the importance of understanding resistance mechanisms to optimize the therapeutic efficacy of capivasertib, suggesting that targeting such neutrophil-tumor cell axis could enhance treatment outcomes.