Ketogenic Diet and β‐Hydroxybutyrate Suppress Bladder Cancer Growth and Enhance Anti‐ PD ‐ L1 Immunotherapy Efficacy

The limited clinical efficacy of immune checkpoint inhibitors (ICIs) remains a major challenge in the treatment of bladder cancer (BCa). Here, we report that a ketogenic diet (KD) and its principal circulating metabolite, β‐hydroxybutyrate (β‐HB), suppress bladder tumor growth and enhance responses to PD‐L1 inhibitor. In a syngeneic MB49 model, KD reduced tumor growth compared with normal diet (ND). KD increased plasma β‐HB and was associated with higher intratumoral PD‐L1 expression. Exogenous β‐HB supplementation under ND recapitulated the antitumor effect of KD, further enhancing anti‐PD‐L1 efficacy. Mechanistically, β‐HB increased intracellular reactive oxygen species (ROS) and disrupted mitochondrial membrane potential in bladder cancer cells, leading to ATP depletion and enhanced apoptosis. Besides, β‐HB also upregulated PD‐L1 in vitro and in vivo through GPR109A‐JAK2‐STAT3 signaling axis. Immune profiling of treated tumors showed increased infiltration and effector function of CD8 + T cells and NK cells and decreased immunosuppressive populations, changes that were further amplified when combined with anti‐PD‐L1. Together, our results indicate that KD and β‐HB exert both tumor intrinsic and immune modulatory effects that sensitize bladder tumors to PD‐L1 inhibitor, supporting further evaluation of ketogenic interventions as adjuvants to immunotherapy in BCa.