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Figure 2. Therapeutic implications of KDM6A deficiency in advanced bladder cancer. Two biologically relevant disease trajectories occur with KDM6A deficiency. First, impaired DNA damage repair results in accumulated DNA damage, chromosomal instability, and an increased mutational burden; this may promote tumor immunogenicity but also renders tumors susceptible to DDR-targeted strategies, including poly(ADP-ribose) polymerase (PARP) inhibition, ataxia telangiectasia and Rad3-related protein/checkpoint kinase 1 (ATR/CHK1) inhibition, and synthetic lethal approaches. Second, KDM6A loss elicits immunometabolic rewiring characterized by reduced glycolysis, reduced lactate production, decreased histone lactylation in Tregs, reduced expansion of PD-1^hi Tregs, and an elevated CD8⁺ T-cell/Treg ratio. These alterations could help explain enhanced responses to PD-1/PD-L1 blockade. KDM6A status, in combination, may further refine therapeutic stratification across chemotherapy, immunotherapy, and rational combination strategies in advanced bladder cancer. Created in BioRender. Zhang H. (2026) https://BioRender.com/79m73os. DSBs: DNA double-strand breaks; DDR: DNA damage repair; HIFα: hypoxia-inducible factor 1 alpha; c-MYC: cellular myelocytomatosis oncogene.