Intermittent fasting reverses T cell lymphopenia via inosine to mitigate brain tumors

Brain tumors are characterized by a paucity of tumor-infiltrating T cells and systemic T cell lymphopenia, both of which contribute to immunotherapy resistance. While dietary restriction modulates immunity, how intermittent fasting (IF) reshapes T cell dynamics in brain tumors remains unknown. Here, we demonstrate that IF reverses T cell lymphopenia by liberating T cells sequestered in the bone marrow, enabling their infiltration into brain tumors and synergizing with anti-PD-1 therapy. Strikingly, this redistribution occurs specifically during the refeeding phase, which is marked by purine metabolic reprogramming and an elevation in circulating inosine levels. Mechanistically, inosine activates adenosine receptor (AR)-PKA signaling in T cells, driving phosphorylation and subsequent lysosomal degradation of CXCR4, the chemokine receptor responsible for bone marrow sequestration. Administering inosine alone recapitulates IF’s effects, restoring peripheral T cell levels and enhancing intratumoral T cell infiltration. Combined with anti-PD-1, inosine achieves robust tumor suppression in glioma and brain metastasis models (breast and lung cancer). Our work uncovers a transformative link between dietary cycles and systemic immunity: fasting-refeeding metabolic fluctuations reprogram T cell trafficking via a purine metabolite, overcoming local and systemic immunosuppression. These insights position inosine as a readily translatable therapeutic strategy to augment immunotherapy efficacy in brain tumors and beyond.