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<p>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<sup>+</sup> T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8<sup>+</sup> 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<sup>+</sup> T cell fate as a key driver of anti-tumour immunity.</p>

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Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月9日

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  • 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 Kaech,
  • H. Josh Jang,
  • Evan C. Lien,
  • Connie M. Krawczyk,
  • Russell G. Jones

摘要

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.