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.
Signal transduction and targeted therapy. 2026 Jul 02*** epublish ***
Takuya Tsujino, Shogo Yamazaki, Moritoshi Sakamoto, Yuki Yoshikawa, Ryoichi Maenosono, Yuki Nakajima, Kensuke Hirosuna, Tomoaki Takai, Kazuki Nishimura, Mitsuaki Ishida, Ko Nakamura, Kengo Iwatsuki, Shuya Tsuchida, Takuya Matsuda, Takuya Higashio, Tatsuo Fukushima, Kyosuke Nishio, Keita Nakamori, Takeshi Tsutsumi, Tomohisa Matsunaga, Kohei Taniguchi, Taiju Shimbo, Tomohito Tanaka, Kiyoshi Takahara, Teruo Inamoto, Yoshinobu Hirose, Fumihito Ono, Kazuhiro Yamamoto, Keiji Nihei, Keigo Osuga, Li Jia, Adam S Kibel, Kazumasa Komura, Akihide Yoshimi, Haruhito Azuma
Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan. ., Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan., Department of Pathology, Osaka Medical and Pharmaceutical University, Osaka, Japan., Center for Medical Research & Development, Division of Translational Research, Osaka Medical and Pharmaceutical University, Osaka, Japan., Department of Radiation Oncology, Osaka Medical and Pharmaceutical University, Osaka, Japan., Department of Urology, Fujita-Health University School of Medicine, Aichi, Japan., Department of Urology, Hamamatsu University School of Medicine, Shizuoka, Japan., Department of Diagnostic Radiology, Osaka Medical and Pharmaceutical University, Osaka, Japan., Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan. ., Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo, Japan. .