Glucose-deprived tumor microenvironment activates AMP-activated protein kinase to drive adoptively transferred T helper 9 cell senescence

T helper 9 (Th9) cells show promise for adoptive cell therapy (ACT) against solid tumors. However, clinical application faces challenges regarding their persistence in the tumor microenvironment (TME). We observed that tumor growth gradually reduced glucose concentrations in the TME, accompanied by a decline in transferred Th9 cells and their effector functions, due to Th9 cell senescence. Restoring glucose concentrations suppressed Th9 cell senescence, thereby improving their persistence. Mechanistically, glucose-deprivation-activated AMP-activated protein kinase (AMPK), triggering downstream leucine-zipper and sterile-α motif kinase (ZAK)-nuclear factor κB (NF-κB)-inducing kinase (NIK) cascades that suppressed noncanonical NF-κB signaling and interleukin (IL)-9 production, ultimately driving Th9 cell senescence. ZAK-associated chimeric antigen receptor (CAR)-T cell senescence was linked to compromised therapeutic efficacy in human cancers. Targeting ZAK rejuvenated Th9 cells and enhanced CAR-Th9 cell efficacy against solid tumors. Our study uncovers a mechanism by which nutrient deprivation promotes Th9 cell senescence to compromise persistence, highlights the potential of targeting ZAK to rejuvenate CAR-Th9 cells for solid tumor therapy.