Ilaha Isali, MD, MSc, discusses sex-specific tumor and immune features in bladder cancer

In this interview, Ilaha Isali, MD, MSc, discusses a narrative review article led by Laura Bukavina, MD, MPH, MSc, that examines growing evidence of sex-specific biological differences in bladder cancer.¹

The review synthesizes data showing that bladder cancer behaves differently in men and women at molecular, immunologic, and epigenetic levels, with important implications for prognosis and treatment. The authors emphasize that sex should be considered a meaningful biological variable in bladder cancer research and in the design of clinical trials.

One of the review’s key findings is that women with non–muscle-invasive bladder cancer experience higher recurrence rates after BCG therapy, whereas women with muscle-invasive disease more frequently exhibit basal squamous tumor subtypes and lower tumor mutational burden. These differences suggest that tumor biology and immune responses vary significantly by sex. Rather than being driven by a single mechanism, the disparities arise from overlapping influences, including epigenetic regulation, immune signaling pathways, and molecular subtype distribution.

The review highlights the role of sex chromosome biology, particularly genes on the X chromosome that escape inactivation. These genes can affect immune function and tumor suppression independently of sex hormones. KDM6A is cited as a notable example, as it links X chromosome biology with chromatin regulation and appears to have sex-specific relevance in bladder cancer progression. Differences in immune checkpoint signaling and macrophage-associated gene expression, especially in female tumors, further underscore sex-dependent immune composition. In muscle-invasive disease, the higher prevalence of basal subtypes in women and associated EGFR signaling pathways suggest distinct tumor–immune interactions.

Importantly, Isali notes that poorer outcomes in female patients cannot be explained solely by hormonal pathways. The review identifies non-endocrine contributors, including sex-specific epigenetic regulation and differences in carcinogen detoxification pathways, such as sulfotransferases and glutathione S-transferase gene variants. Together, these findings demonstrate that biological differences extend well beyond hormones and may significantly influence tumor development, disease progression, and treatment response, particularly in female bladder cancer patients.

REFERENCE

1. Isali I, Khooblall P, Helstrom E, Bukavina L. Targeting bladder cancer: A sex sensitive perspective in mutations and outcomes. Urol Oncol. 2025;43(12):673-679. doi:10.1016/j.urolonc.2023.05.008