Multilayered analysis of cisplatin resistance mechanisms in bladder cancer: from the cell membrane to organelles

Bladder cancer (BCa) is one of the most common malignancies of the urinary tract worldwide. Cisplatin-based combination chemotherapy remains a cornerstone of treatment for muscle-invasive and advanced disease and has substantially improved clinical outcomes, yet primary and acquired resistance frequently leads to treatment failure and disease recurrence. Classical mechanisms, including altered drug uptake and efflux and detoxification by glutathione or metallothioneins, account for only part of this phenotype. Recent work in BCa increasingly points to cisplatin resistance as a multilayered cellular adaptation involving coordinated changes in drug handling, stress responses, and cell-death control. Drawing primarily on studies published between January 2020 and April 2025, while incorporating selected foundational studies from the preceding decade, this review maps cisplatin resistance in BCa within a structured “cell membrane and tumor microenvironment–cytoplasm–nucleus and chromatin–organelles” framework. Particular emphasis is placed on the interaction of epithelial–mesenchymal transition and cancer stem cell programs with stromal and immune signals at the membrane level; on metabolic rewiring, ferroptosis regulation, and stress-activated signaling cascades in the cytoplasm; on reinforced DNA damage response pathways and RNA- or chromatin-directed epigenetic remodeling in the nucleus; and on the resetting of apoptotic, autophagic, and mitophagic thresholds at the organelle level. Across these compartments, recurrent regulatory nodes and signaling axes are outlined, and areas are delineated where mechanisms are supported by convergent in vitro , in vivo , and clinical evidence versus those that remain primarily exploratory. By viewing cisplatin resistance in BCa as an integrated and dynamic network spanning cellular compartments, this multilayered synthesis aims to refine current mechanistic concepts and to provide a rationale for biomarker development and combination strategies designed to prevent or overcome cisplatin resistance.