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.