Immune Phenotype in Urothelial Carcinoma: From Tumor Biology to Therapeutic Stratification.

Urothelial carcinoma (UC) is a biologically and clinically heterogeneous disease arising from the bladder and upper urinary tract. Immune checkpoint inhibitors (ICIs) have transformed treatment of advanced UC, yet durable responses remain limited to a minority of patients, underscoring the need to better understand the tumor immune microenvironment (TME). This narrative review examines the UC immune phenotype across disease stages and anatomical sites, integrating evidence from bulk and single-cell transcriptomics, spatial profiling, and translational studies. We describe the principal immune cell populations of the UC TME-including cytotoxic and regulatory T cells, macrophages, myeloid-derived suppressor cells, natural killer cells, B cells, and dendritic cells-and their relationship to established molecular subtypes. We review how this immune landscape evolves from non-muscle-invasive to metastatic disease, including the distinct contexture of upper tract UC and variant histology. We critically evaluate established ICI biomarkers (PD-L1, FGFR3, tumor mutational burden, mismatch repair deficiency) alongside emerging candidates-tumor-infiltrating lymphocyte density, HLA class I expression, tertiary lymphoid structures, and multiparameter transcriptomic scores-noting that most remain investigational and require prospective validation before clinical use. Finally, we address key biological, technical, and clinical barriers to this research and outline future directions in AI-assisted digital pathology and multimodal biomarker integration. A comprehensive characterization of UC immune phenotype is essential to guide rational, biomarker-driven patient selection and optimize next-generation immunotherapy strategies.