biostudies-literatureUnknown14(2)Moravej H<h4>Background</h4>Limited durability of clinical responses remains a major challenge in chimeric antigen receptor (CAR)-T therapy. CAR-enhancers (CAR-Es), which fuse tumor antigens to interleukin (IL)-2 muteins, provide a targeted strategy to enhance CAR-T persistence and function. It remained unclear whether CAR-Es are effective across distinct tumor contexts, when using patient-derived T cells, or in preventing exhaustion and sustaining persistence. It was also unknown whether CAR-Es can selectively expand CAR-Ts in humanized mice with pre-existing T cells, and to what extent their efficacy depends on IL-2Rβγ vs IL-2Rα engagement. While IL-2Rα (CD25) has been classically linked to potent antitumor responses and memory formation, it also drives IL-2-associated toxicities, including vascuJournal for immunotherapy of cancere013665https://www.ebi.ac.uk/biostudies/studies/S-EPMC12918668biostudies-literatureAntigen-IL-2 CAR-enhancer drives CAR-T fate and stemness, enhancing antitumor efficacy across models independent of IL-2Rα.PMC12918668Moravej HRivet VMNia HTFulciniti MKowalewski ANadeem OBerland LMantri SRMunshi NCKhan RMMJacobson CABaral JMarcandalli EMunaretto LALee UJWolff ANGabr ZTaklifi PSperling ASHemann MAllen HHNili AFarkash ZMercadante DLouis BBVRashidian MRakhshandehroo TRegan KfalseAntigen-IL-2 CAR-enhancer drives CAR-T fate and stemness, enhancing antitumor efficacy across models independent of IL-2Rα.<h4>Background</h4>Limited durability of clinical responses remains a major challenge in chimeric antigen receptor (CAR)-T therapy. CAR-enhancers (CAR-Es), which fuse tumor antigens to interleukin (IL)-2 muteins, provide a targeted strategy to enhance CAR-T persistence and function. It remained unclear whether CAR-Es are effective across distinct tumor contexts, when using patient-derived T cells, or in preventing exhaustion and sustaining persistence. It was also unknown whether CAR-Es can selectively expand CAR-Ts in humanized mice with pre-existing T cells, and to what extent their efficacy depends on IL-2Rβγ vs IL-2Rα engagement. While IL-2Rα (CD25) has been classically linked to potent antitumor responses and memory formation, it also drives IL-2-associated toxicities, including vascu2026-01-01T00:00:00Z2026 Feb2026-07-16T09:17:29.707Z2026-07-09T10:46:51.594ZS-EPMC129186684170814510.1136/jitc-2025-013665