Preclinical studies have shown that acute asparagine deprivation can disrupt protein synthesis and intracellular signaling in a manner that compromises CD8+ T cell activation, but prolonged deprivation induces metabolic reprogramming that has the opposite effect. Researchers led by Ludwig Lausanne’s Ping-Chih Ho and a colleague of his in Taiwan examined whether the latter effect might be harnessed to improve responses to immune checkpoint blockade (ICB) therapy. They reported in a March Nature Metabolism paper their findings from an open-label study that treated a few patients with recurrent metastatic nasopharyngeal carcinoma with L-asparaginase, which degrades asparagine and is used to treat blood cancers. Six patients resistant to anti-PD-1 ICB therapy received asparaginase injections for 3 or 5 days followed by the anti-PD-1 therapy pembrolizumab, and were compared with patients receiving only anti-PD-1 therapy. L-asparaginase fortified CD8+ T cell fitness and enhanced patient responses to ICB, with progression-free survival of at least 10.5 months compared to 2 months for ICB alone. Studies using mouse models of other cancers showed that asparaginase boosts the efficacy of anti-PD-1 by enhancing T cell activation. The researchers reported that acute and prolonged asparagine deprivation have opposite effects on mitochondrial health and biogenesis as well as T cell differentiation patterns and detailed the extensive metabolic rewiring that enhances T cell anti-tumor activity.
Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations
Nature Metabolism, 2025 March 5