A ferroptosis-suppressive tumor state to drive chemoradiotherapy resistance and define a therapeutic vulnerability in muscle-invasive bladder cancer.
Takuya Tsujino, Shogo Yamazaki, Tomoaki Takai, Kazuki Nishimura, Kazumasa Komura, Akihide Yoshimi, Haruhito Azuma,195
Background:
Bladder-preserving chemoradiotherapy (CRT) is a curative alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), yet durable disease control is limited by intrinsic resistance whose basis remains unclear.
Methods:
We performed transcriptomic profiling of pretreatment tumors from 179 patients uniformly treated with CRT and integrated gene expression with clinical outcomes, molecular subtype features, and immune contexture. Functional validation used CRT-resistant bladder cancer models and genome-wide CRISPR/Cas9 knockout screening under irradiation (IR).
Results:
We identified a ferroptosis-suppressive transcriptional signature (FSS) that defines a distinct resistance state and independently predicts radiographic progression-free and overall survival after CRT. High-FSS tumors showed inferior outcomes and were enriched for basal/squamous and immune-excluded phenotypes with reduced immune infiltration. This state was recapitulated in experimentally derived CRT-resistant models. CRISPR screening under IR identified core ferroptosis suppressor genes as essential survival dependencies and radiosensitizers, and pharmacologic ferroptosis induction restored radiosensitivity in resistant cells.
Conclusions:
A ferroptosis-suppressive state represents a mechanistically defined resistance program linking tumor-intrinsic transcriptional circuitry, immune microenvironment architecture, and therapeutic vulnerability. These findings establish ferroptosis regulation as a clinically actionable axis for risk stratification and therapeutic intensification in bladder-preserving MIBC.
Multivariable Cox models evaluating clinicopathologic factors and FSS for radiographic progression-free survival.