Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8 T cell-mediated anti-tumor immunity. DR reshapes CD8 T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth. Mechanistically, DR enhances CD8 T cell metabolic fitness through increased ketone body oxidation (ketolysis), which boosts mitochondrial membrane potential and fuels tricarboxylic acid (TCA) cycle-dependent pathways essential for T cell function. T cells deficient for ketolysis exhibit reduced mitochondrial function, increased exhaustion, and fail to control tumor growth under DR conditions. Our findings reveal a critical role for the immune system in mediating the anti-tumor effects of DR, highlighting nutritional modulation of CD8 T cell fate in the TME as a critical determinant of anti-tumor immunity.
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| http://dx.doi.org/10.1101/2024.11.14.621733 | DOI Listing |
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