Ketogenic Fasting Suppresses Tumor Growth and Enhances PD-1 Blockade Efficacy Through Glutamine Partitioning and Microbial Metabolite Remodeling

Many tumors remain poorly responsive to immune checkpoint blockade. The metabolic microenvironment in tumors can mediate immunosuppression by failing to sustain productive cytotoxic lymphocyte function. Here, we showed that a coordinated ketogenic-fasting (KF) regimen sensitized immune-refractory tumors to PD-1 blockade by integrating distinct metabolic and microbial effects of ketogenic diet (KD) and intermittent fasting (IF). The KF combination established a distinct immunometabolic state that could not be fully recapitulated by either KD or IF intervention alone. KF induced systemic glucose restriction while preserving intratumoral glutamine availability and selectively upregulating the glutamine transporters SLC38A1 and SLC38A2 in tumor-infiltrating CD8+ T cells and NK cells, fueling interferon-STAT1 signaling and effector activity. Single-cell transcriptomic analysis identified KF-associated cytotoxic lymphocyte states characterized by enhanced nutrient access signatures, increased effector function, and reduced terminal dysfunction. Microbiota depletion attenuated KF-mediated tumor control without abolishing intratumoral glutamine enrichment. Fecal microbiota transfer and monocolonization identified Odoribacter splanchnicus as sufficient to restore tumor control and cytotoxic T-cell activity in microbiota-depleted hosts. Mechanistically, O. splanchnicus was linked to host polyamine remodeling and indole-3-lactic acid, which supported durable CD8+ T-cell functions distinct from the glutamine-driven effector arm. KF enhanced anti-PD-1 efficacy in immune-cold tumor models, and public human datasets showed concordant associations between glutamine context, Odoribacter abundance, and immunotherapy response. Together, these findings identify a diet-responsive host-microbiota metabolic mechanism that stimulates antitumor immunity and sensitizes immune-cold tumors to immunotherapy.