Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses
Brandon M. Oswald, Lisa M. DeCamp, Joseph Longo, Michael S. Dahabieh, Nicholas Bunda, Benjamin K. Johnson, McLane J. Watson, Shixin Ma, Samuel E.J. Preston, Ryan D. Sheldon, Michael P. Vincent, Abigail E. Ellis, Molly T. Soper-Hopper, Christine Isaguirre, Dahlya Kamarudin, Hui Shen, Kelsey S. Williams, Peter A. Crawford, Susan M. Kaech, H. Josh Jang, Evan C. Lien, Connie M. Krawczyk, Russell G. Jones
Abstract
Abstract Reducing calorie intake through dietary restriction (DR) slows tumour growth in mammals, yet the underlying mechanisms are poorly defined. Here, we show that DR enhances anti-tumour immunity by optimizing CD8 + T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8 + T cell fate in the TME, favouring the expansion of effector T cell subsets with enhanced metabolic capacity and cytotoxic potential, while limiting the accumulation of terminally exhausted T cells. This metabolic reprogramming is driven by enhanced ketone body oxidation, particularly β-hydroxybutyrate (βOHB), which is elevated in both the circulation and tumour tissues of DR-fed mice. βOHB fuels T cell oxidative metabolism under DR, increasing mitochondrial membrane potential and tricarboxylic acid cycle-dependent pathways critical for T cell effector function, including acetyl-CoA production. By contrast, T cells deficient for ketone body oxidation exhibit reduced mitochondrial function, increased exhaustion and fail to control tumour growth under DR conditions. Importantly, DR synergizes with anti-PD1 immunotherapy, further augmenting anti-tumour T cell responses and limiting tumour progression. Our findings reveal that T cell metabolic reprogramming is central to the anti-tumour effects of DR, highlighting nutritional control of CD8 + T cell fate as a key driver of anti-tumour immunity.