Spatiotemporal dynamic evolution of the tumor microenvironment during neoadjuvant immunotherapy for bladder cancer

We characterize the spatiotemporal dynamics of the tumor microenvironment (TME) in bladder cancer (BLCA) samples before and after neoadjuvant immunotherapy in a multicenter real-world cohort (n = 606). We identify two distinct differentiation outcomes in BLCA epithelial cells: sensitivity and resistance to immunotherapy. Additionally, we identify SERPINH1 as a common target of acquired immunotherapy resistance in BLCA. Furthermore, we characterize an immunotherapy-induced tumor-myeloid barrier, which leads to an excluded immune phenotype and immunotherapy resistance. Finally, we identify T cell terminal exhaustion and a senescent inflammatory cancer-associated fibroblast phenotype as key factors contributing to immunotherapy resistance. Collectively, we reveal the dynamic phenotypic evolution of the TME in BLCA during neoadjuvant immunotherapy and identify the characteristics of residual lesions after immunotherapy. These findings enrich our understanding of immunotherapy resistance in BLCA and contribute to developing combination therapies to improve patient prognosis.