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 (UC), yet response rates remain limited. Inflammation promotes disease progression and treatment resistance, with macrophages shaping the tumor microenvironment (TME). While elevated blood C-reactive protein (CRP) associates with poor clinical outcomes in UC, its relationship to the TME remains unclear. Here, we show that elevated plasma IL-6 and CRP associate with increased tumor macrophage infiltration across multiple ICB-treated cohorts. Single-cell RNA sequencing of the largest UC atlas to date, integrated with bulk RNA sequencing, identifies enrichment of immunosuppressive SPP1+ macrophages in TMEs from patients with high plasma IL-6. Spatial and functional analyses demonstrate that SPP1+ macrophages suppress T cell activity partly via IL-6 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 UC.