Bladder cancer (BCa) is one of the most sexually dimorphic malignancies. The epidemiological paradox is striking, with men showing a 3- to 4-fold higher incidence than women, whereas women consistently present with more advanced disease and experience worse stage-for-stage survival outcomes.1 For decades, this gap has been attributed to extrinsic factors such as smoking and occupational hazards. However, as these exposures have converged between sexes without narrowing of the incidence gap, the field has pivoted toward intrinsic biological and molecular drivers, particularly the interplay between sex chromosomes, hormones, and the immune microenvironment.2 In this issue of Current Urology, Harland et al. provided a new critical piece of this biological puzzle. Their exploratory study revealed that CD276 (i.e., B7-H3), a potent immune checkpoint molecule associated with tumor aggressiveness, was significantly overexpressed in male bladder tissues compared with that in female tissues.3 While this finding is significant on its own, its true value lies in how it contextualizes the divergent evolutionary paths of male and female BCa tumors, suggesting that the “androcentric” biology of BCa may also rely on distinct immune evasion mechanisms compared with their female counterparts, challenging the utility of sex-blind immunotherapy strategies. 1. The male phenotype: androgens, CD276, and Y chromosomal loss The upregulation of CD276 in men is consistent with a growing body of evidence implicating the androgen receptor (AR) axis in immunosuppression. As noted in recent reviews by Chaudhary et al.,2 androgens are not only proliferative drivers, but also architects of the immunosuppressive tumor microenvironment (TME). For example, AR signaling promotes CD8+ T-cell exhaustion via Tcf7 regulation and can directly upregulate checkpoint molecules.2 However, the male-specific landscape was further complicated by the notable loss of Y (LOY). Recent breakthrough work by Chen et al. 4 has fundamentally shifted our understanding of LOY from a passive marker of aging to an active driver of neoplasia involving immune TME remodeling. They demonstrated that LOY is not restricted to malignant epithelial cells, through which immune escape is possibly provoked by epigenetic remodeling associated with LOY-locating key regulators (e.g., UTY and KDM5D), but is pervasive in the TME as well, particularly in CD8+ T cells, where it drives an exhausted, dysfunctional phenotype.4,5 This suggests a potentially “vicious cycle” in male BCa, as high androgen levels may induce CD276 expression, shielding the tumor,6 while concurrent LOY in T cells weakens the antitumor response. Nevertheless, although LOY drives aggressive biology, it may also sensitize tumors to immune checkpoint blockade because LOY-driven tumors often exhibit a high tumor mutational burden and genomic instability.4,5 Harland et al. found elevated CD276 levels in males, suggesting that male BCa might be uniquely vulnerable to combinatorial strategies targeting both the AR axis to downregulate CD276 and block the programmed cell death protein-1/programmed cell death ligand-1 axis to reinvigorate LOY-exhausted T cells (Fig. 1).Figure 1.: Schematic representation of sex-divergent molecular mechanisms in bladder cancer. (A) The male phenotype, characterized by high expression of the immune checkpoint CD276 (B7-H3) on the cell surface and androgen receptor (AR) signaling within the nucleus. The loss of Y (LOY) chromosome contributes to immune evasion and T-cell exhaustion. Therapeutic implications include combinatorial anti-AR, anti-CD276, and anti–programmed cell death protein-1 (PD-1) therapies. (B) The female phenotype, characterized by enrichment of mutations in FGFR3 as well as in the X-linked KDM6A gene, leading to epigenetic remodeling. This landscape suggests a potential benefit from small-molecule FGFR inhibitors or epigenetic modulators rather than checkpoint blockade alone.2. The female phenotype: FGFR3 mutations and X-linked epigenetic remodeling If men rely on CD276- and LOY-mediated evasion, then what drives female BCa from an immune perspective? The lower CD276 expression in women observed by Harland et al. suggests that CD276-targeted monotherapy may fail in female cohorts. This necessitates the examination of the distinct molecular landscape of the female bladder. Complementary data from our previous meta-analysis highlighted that female patients with BCa harbor a significantly higher frequency of FGFR3 somatic mutations, specifically the S249 and Y375 hotspots, than men.7 Furthermore, Calvet et al. 8 used ultra-deep duplex sequencing to reveal that the normal urothelium undergoes sex-biased clonal expansion, identifying stronger positive selection in genes such as RBM10 and CDKN1A in men, in contrast to the female-specific enrichment of X-chromosome-locating KDM6A mutations often observed in established tumors. Biologically, females generally possess a more robust innate and adaptive immune response than males despite comparable APOBEC3- and tobacco-related mutational burden.9,10 Therefore, for a tumor to survive in a female host, it may be necessary to select nonimmunogenic drivers, such as FGFR3 activating mutations that have been shown to be linked with an immune-cold phenotype or deep epigenetic remodeling via KDM6A loss, rather than relying solely on checkpoint upregulation, such as CD276. This divergence suggests that women respond differently to standard immunotherapies and may be better candidates for combinatorial strategies, including immune checkpoint blockade and fibroblast growth factor receptor (FGFR) inhibition or epigenetic modulation (Fig. 1). 3. Toward sex-informed clinical decisions The divergence in the immune landscapes described by Harland et al., combined with genomic insights from previous studies, compelled us to adopt sex as a stratification factor in clinical practice. First, biomarker screening may need to evolve. In men, screening for LOY in the peripheral blood (as a surrogate for TME Y status) and CD276 expression could identify candidates for combinatorial therapies targeting the AR axis and immune checkpoints. Conversely, in women, the enrichment of FGFR3 mutations and KDM6A alterations suggests a higher priority for FGFR inhibitors (e.g., erdafitinib) or epigenetic modulators, potentially as earlier lines of therapy, given their lower baseline CD276 expression levels. Ultimately, Harland et al. have challenged the “androcentric” norm of BCa biology, which does not apply universally, along with other emerging evidence. To improve the outcomes for women who have historically fared worse, we should consider a transition from sex-blind protocols to sex-informed precision oncology that recognizes these fundamental biological distinctions. Acknowledgments None. Statement of ethics Not applicable. Conflict of interest statement Generative AI Gemini 3 Pro and Nano-Banana Pro were used to aid manuscript and figure preparation, under the full control and manipulation of the human authors. MS is a member of the Early Career Editorial Board of Current Urology and confirms no involvement in any stage of this article’s review process, ensuring unbiased editorial decision-making. The remaining authors have no conflicts of interest to disclose. Funding source XM was supported by the National Natural Science Foundation of China (82303057) and the “Chutian Scholars Program” of Hubei Province, China. MS was supported by the National Natural Science Foundation of China (No.82373436), Beijing Physician Scientist Training Project (BJPSTP-2025-39), Beijing Key Clinical Specialty Development Project (20240930), and the National Key Clinical Specialty Development Project (20250829). Author contributions All authors contributed to the conceptualization and writing of the manuscript, and have read and agreed to the published version of the manuscript. Data availability Not applicable.
Meng et al. (Fri,) studied this question.