PTEN-low associated mismatch repair deficiency and nuclear PD-L1 expression in basal-type bladder cancer

Molecular subtyping is critical for prognostic stratification and treatment in bladder cancer (BCa). However, few studies have combined immunohistochemistry (IHC)-based subtyping with spatial immune profiling and predictive biomarker evaluation. In this study, we retrospectively analyzed 109 BCa patients using a three-part profiling strategy: (1) molecular classification into basal, luminal, double-positive (DP), and double-negative (DN) subtypes with basal (CK5/6, CD44) and luminal (CK20, GATA3) markers, merging DP tumors with basal for analysis; (2) assessment of tumor biology by evaluating p53, PTEN, PD-L1, and mismatch repair (MMR) proteins; (3) multiplex IHC and digital pathology-assisted spatial quantification of immune cells. Basal-subtype tumors showed frequent PTEN loss (P = 0.032) and a novel nuclear PD-L1 pattern (P = 0.043) linked to chemoresistance and recurrence (P = 0.049). MMR profiling revealed reduced PMS2 expression (P < 0.0001) and coordinated downregulation of MMR proteins in PTEN-low tumors. Immune analysis indicated an immune-hot phenotype, but nuclear PD-L1 positivity did not correlate with T-cell density. This study highlights the significance of PTEN loss and nuclear PD-L1 expression in basal subtype BCa, contributing to improved risk stratification and potential precision treatments in bladder cancer.