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Asparagine Deprivation Enhances T Cell Antitumour Response in Patients

via ROS-Mediated Metabolic and Signal Adaptations

1
1
Hsuan-Chia Chang, Chung-Ying Tsai, Huang-Yu Yang* ,1,2

1 Kidney Research Center and Department of Nephrology, Chang Gung Memorial Hospital,
Taoyuan, Taiwan.
2 Institute of Immunology and Translational Medicine, Chang Gung University, Taoyuan,
Taiwan

* E-mail: hyyang01@gmail.com

Abstract
Nutrient availability plays a crucial role in T cell activation, with amino acid metabolism
being regulated by multiple signaling pathways. Beyond serving as building blocks for protein

synthesis, amino acids contribute to biomaterial generation and biochemical modifications.
However, the impact of amino acid deprivation on T cell activation remains poorly understood.
In this study, we demonstrate that asparagine deprivation delays CD8 T cell activation and
induces metabolic reprogramming. ATAC-seq analysis revealed an enrichment of NFAT and

AP-1 transcription binding motifs under asparagine-deprived conditions. Mechanistically,
asparagine deprivation resulted in mitochondrial complex I deficiency and ROS production,
driving NFAT nuclear translocation and enhancing T cell activation. ROS scavenging with NAC
rescued the stress response signaling and restored anti-tumor activity, indicating that ROS

modulates metabolic adaptation during asparagine restriction. Immune checkpoint inhibitors
(ICIs) have shown remarkable efficacy in treating various cancers, but their effectiveness in
recurrent-metastatic nasopharyngeal carcinoma (RM-NPC) remains limited. Combination
therapies integrating ICIs with other modalities have improved outcomes in several

malignancies. Here, we found that asparaginase combined with pembrolizumab significantly
improved progression-free survival (PFS) and objective response rate (ORR) in RM-NPC
patients compared to pembrolizumab monotherapy. Furthermore, a decline in EBV DNA copy
number following combination therapy suggests enhanced T cell activation and inhibition of

tumor progression. Altogether, our findings highlight the adaptive mechanisms of T cells under
asparagine deprivation and provide a compelling rationale for leveraging this metabolic
vulnerability to enhance cancer immunotherapy.

Keywords: Asparagine; CD8 T cell; ROS

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