A Tumor-Promoting Inflammatory SPP1 + Macrophage–IL6–CRP Axis Drives Immune Dysfunction in Bladder Cancer

Immune checkpoint blockade (ICB) has revolutionized treatment for urothelial bladder cancer, yet response rates remain limited. Inflammation promotes disease progression and treatment resistance, with macrophages shaping the tumor microenvironment (TME). Although elevated blood C-reactive protein (CRP) is associated with poor clinical outcomes in urothelial bladder cancer, its relationship to the TME remains unclear. In this study, we show that elevated plasma IL6 and CRP associate with increased tumor macrophage infiltration across multiple ICB-treated cohorts. Single-cell RNA sequencing (RNA-seq) of the largest urothelial bladder cancer atlas to date, integrated with bulk RNA-seq, identifies enrichment of immunosuppressive SPP1+ macrophages in TMEs from patients with high plasma IL6. Spatial and functional analyses demonstrate that SPP1+ macrophages suppress T-cell activity partly via IL6 signaling, whereas CXCL9+ macrophages promote T-cell activation. These findings link systemic inflammation to local immune dysfunction and define a macrophage-driven axis associated with ICB resistance and therapeutic targets to improve immunotherapy outcomes in urothelial bladder cancer. SIGNIFICANCE: Single-cell and bulk RNA-seq, spatial analyses, and functional experiments identify opposing SPP1+ and CXCL9+ macrophage programs that regulate T-cell function and ICB therapy response in bladder cancer. Elevated plasma CRP and IL6 mark SPP1+ macrophage-driven immune suppression, defining a targetable IL1β/IL6 axis that contributes to immunotherapy resistance.