Countering T cell exhaustion and senescence for enhanced adoptive T cell therapies against solid tumors

Abstract

CAR-T cell therapy has shown remarkable success in treating hematopoietic malignancies, but its efficacy in solid tumors is limited by T cell dysfunction, including exhaustion and senescence. In this study, we designed metabolically armored CAR-T cells to counter exhaustion-associated dysfunction in the tumor microenvironment (TME). IL-10-engineered CAR-T cells exhibited enhanced mitochondrial fitness and oxidative phosphorylation activities in the TME. IL-10 secretion significantly improved CAR-T cell proliferation and effector function, leading to complete regression of established solid tumors in mouse models. Furthermore, IL-10 CAR-T cells induced stem cell-like memory responses, providing durable protection against tumor rechallenge. Additionally, we demonstrated that IL-4-armored CAR-T cells, which are a type 2 cytokine, enhanced glycolysis and effector function, enabling the eradication of established solid tumors in syngeneic and xenograft mouse models. These findings present a promising approach to overcome CAR-T cell exhaustion through metabolic armoring, addressing a significant challenge in adoptive T cell therapy. Moreover, we investigated how T cell senescence in tumors is contributed to by both aging factors and TME-induced premature senescence. We found that IL-10-Fc treatment effectively prevented T cell senescence and enhanced the antitumor efficacy of ACT therapy. This study offers a potential therapeutic strategy to restore immune function and combat malignancies and infections in older individuals.