A ferroptosis-suppressive state drives resistance to bladder-preserving chemoradiotherapy in muscle-invasive bladder cancer.

Bladder-preserving trimodality therapy (TMT) incorporating concurrent chemoradiotherapy (CRT) provides a curative-intent alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), yet its efficacy is frequently limited by intrinsic treatment resistance, the molecular basis of which remains poorly defined. To address this, we performed bulk transcriptomic profiling of pretreatment tumors from 179 patients uniformly treated with bladder-preserving CRT and systematically integrated gene expression data with tumor immune features and clinical outcomes. We identified a ferroptosis-suppressive transcriptional signature (FSS) associated with a distinct resistance-associated tumor state that independently stratified radiographic progression-free survival and overall survival following CRT. FSS-high tumors were characterized by inferior outcomes, enrichment of basal/squamous and immune-excluded phenotypes, and reduced intratumoral immune infiltration, whereas FSS-low tumors preferentially exhibited luminal unstable and immune-inflamed features. Consistent with clinical observations, a ferroptosis-suppressive transcriptional program was recapitulated in CRT-resistant bladder cancer cell line models. Genome-wide CRISPR/Cas9 loss-of-function screening further identified core ferroptosis suppressors as functionally relevant dependencies specifically under irradiation stress, and pharmacologic induction of ferroptosis effectively restored radiosensitivity in otherwise resistant cells. Together, these findings support ferroptosis suppression as a biologically relevant resistance-associated state that mechanistically links tumor-intrinsic transcriptional programs to immune contexture and therapeutic vulnerability and provide a translational framework for improved risk stratification and future treatment refinement in bladder-preserving therapy for MIBC.