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4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8⁺ T cell antitumor response

Jihae Ahn,¹ Ping Xie,¹ Siqi Chen,¹ Guilan Shi,¹ Jie Fan,¹ Minghui Zhang,¹ Hui Tang,¹ Amanda R. Zuckerman,¹ Deyu Fang,² Yong Wan,³ Timothy M. Kuzel,¹ Yi Zhang,⁴ and Bin Zhang¹

Published April 3, 2025 - More info

Activating the immune co-stimulatory receptor 4-1BB (CD137) with agonist antibody binding and crosslinking-inducing agents that elicit 4-1BB intracellular signaling potentiates the antitumor responses of CD8 T cells. However, the underlying in-depth mechanisms remain to be defined. Here, we show that agonistic 4-1BB treatment of activated CD8⁺ T cells under continuous antigenic stimulation are more metabolically vulnerable to redox perturbation by ablation of intracellular glutathione (GSH) and glutathione peroxidase 4 (GPX4) inhibition. Further, genetic deletion of adenosine A2B receptor (A2BR) induces superior survival and expansion advantage of competent CD8⁺ T cells with agonistic 4-1BB costimulation, leading to more effective antitumor efficacy of adoptive cell therapy (ACT). Mechanistically, A2BR deletion helps sustain the increased energy and biosynthetic requirements through the GSH-GPX4 axis upon 4-1BB costimulation. A2BR deletion in combination with agonistic 4-1BB costimulation displays a greater ability to promote antitumor CD8⁺ effector T cell survival and expansion while mitigating T cell exhaustion. Thus, the A2BR pathway plays an important role in metabolic reprogramming with potentiation of the GSH-GPX4 cascade upon agonistic 4-1BB costimulation that allows the fine-tuning of the antitumor responses of CD8⁺ T cells.

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