Immune checkpoint inhibitors (ICIs) have shown promising results in
bladder cancer (BC). However, only some patients respond to ICIs. DNA repair defects (DDR) play an important role in the therapeutic response of
bladder cancer. Therefore, we aimed to elucidate the association between ICIs in
bladder cancer and
ataxia telangiectasia mutated (ATM), a core component of the DNA repair system. From a collected
immunotherapy cohort (n = 210) and The
Cancer Genome Atlas (TCGA)-
Bladder cancer cohort, which were both retrieved from publicly available resources, we performed a series of analyses to evaluate the prognostic value and potential mechanism of ATM in
bladder cancer immunotherapy. We found that ATM-mutant (ATM-MT)
bladder cancer patients derived greater benefit from ICIs [overall survival (OS), hazard ratio (HR) = 0.28, [95% confidence interval (CI), 0.16 to 0.51], P = 0.007] and showed a higher mutation load (P < 0.05) and immunogenicity (P < 0.05) than ATM-wild-type (ATM-WT) patients. The immune inflammatory response to antigenic stimulation, the regulation of the IFN pathway and the macrophage activation pathway were significantly enriched in the ATM-MT group (NES > 1, P < 0.05), while
insulin-like growth factor receptor signaling pathways and vasculogenesis were significantly downregulated (NES < -1, P < 0.05). ATM mutation significantly upregulated the number of DNA damage repair pathway gene mutations (P < 0.05). ATM mutations resulted in increased
bladder cancer sensitivity to 29 drugs (P < 0.05), including
cisplatin and
BMS-536924, an IGF-1R inhibitor. Our results demonstrate the importance of ATM as a prognostic signature in
bladder cancer and reveal that ATM may impact the effects of ICIs by acting on the
tumor immune microenvironment.