How sex influences the bladder cancer tumor microenvironment

In this interview, Ilaha Isali, MD, MSc, discusses emerging evidence highlighting the importance of sex-specific biology in bladder cancer, particularly within the tumor microenvironment (TME), response to immunotherapy, and future directions for precision medicine.¹

Isali emphasizes that one of the most consistent findings across studies is that high-grade bladder tumors in women exhibit increased expression of immune checkpoint genes and greater infiltration of tumor-associated macrophages, especially among patients with early disease recurrence. Although immune cells are present, their activity may be functionally suppressed, suggesting an immunosuppressive TME. This phenomenon may partially explain why immunotherapies, including checkpoint inhibitors, often show reduced durability or effectiveness in female patients. These findings underscore the need to move beyond simply measuring immune presence and toward understanding immune behavior and functional states within the TME.

When discussing sex differences in response to BCG and other immunotherapies, Isali notes that the most promising predictive biomarkers are not single mutations but composite genomic and immune signatures. X-linked immune genes involved in checkpoint regulation may help explain higher recurrence rates in women, particularly during BCG maintenance therapy. Additionally, immune checkpoint expression patterns, macrophage-related signatures, and lower tumor mutational burden—more commonly observed in female patients with muscle-invasive disease—may limit responsiveness to immunotherapy. She highlights genes such as KDM6A as examples of how sex-linked genomic architecture can influence treatment outcomes, advocating for sex-aware biomarker strategies rather than one-size-fits-all models.

Finally, Isali identifies major unresolved gaps in sex-specific bladder cancer research. She stresses that sex must be treated as a true biological variable, not merely a statistical adjustment, with intentional inclusion of women in clinical trials. The most urgent unanswered question remains why female patients—particularly those with non–muscle-invasive bladder cancer—experience higher recurrence rates and reduced responses to immunotherapy. Clarifying whether these differences are driven by tumor-intrinsic features, immune suppression within the TME, or a combination of both will be essential for developing truly actionable, sex-stratified precision medicine approaches.

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