Senescent bladder cancer cells promote acquired cisplatin resistance by facilitating macrophage infiltration

Background: Cisplatin-based chemotherapy represents the standard first-line treatment for muscle-invasive bladder cancer. However, the mechanisms underlying acquired resistance remain incompletely understood. Objective: This study explored the role of chemotherapy-induced senescence in shaping a tumor microenvironment that fosters resistance. Methods: Cisplatin-induced cellular senescence in bladder cancer cells was investigated by activating the nuclear factor κ-light-chain-enhancer of activated B cells signaling pathway and assessed by β-galactosidase staining, enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction, and Western blotting. Results: Transwell migration assays and bioinformatic analyses revealed that these senescent cells secreted factors that enhanced macrophage recruitment. Mechanistically, senescence led to the downregulation of the androgen receptor (AR) gene, which in turn facilitated macrophage infiltration. Intriguingly, the recruited macrophages subsequently upregulated AR expression in cancer cells, ultimately diminishing their sensitivity to cisplatin, as shown in Cell Counting Kit-8 assays and molecular profiling. The findings reveal a novel “senescence–macrophage–chemoresistance” axis in bladder cancer, wherein cisplatin-induced senescent cells drive treatment failure by promoting macrophage-dependent AR signaling and chemoresistance. Conclusion: These findings provide valuable insights for the development of novel therapeutic strategies for overcoming cisplatin resistance in muscle-invasive bladder cancer.