Spatial architecture contributes to failure of bulk biomarker-guided neoadjuvant immunotherapy selection in bladder cancer: The DUTRENEO study

作者：Enrique Grande, Mustafa Sibai, Daniela Grases, Elena Andrada, Òscar Reig, Marc Escobosa, Ainara Azueta, Daniel Castellano, Javier Puente, Jaime Martínez de Villarreal, Albert Font, Teresa Alonso‐Gordoa, Raquel Benítez, Ane Moreno-Oya, Mario Álvarez-Maestro, Javier Burgos, MA Climent, M. Domínguez, Patricia Galván, Isabel Galante, Juan F García, Elena Perez, Xavier García del Muro, Félix Guerrero‐Ramos, Mirari Marques, Pablo Maroto, Jesús M. Paramio, Álvaro Pinto, Aleix Prat, Núria Malats, Ignacio Durán, Eduard Porta‐Pardo, Francisco X. Real · 发表于：Cell Reports Medicine · 年份：2026 · DOI：10.1016/j.xcrm.2026.102878 · 被引用次数：3 · 研究领域：Bladder and Urothelial Cancer Treatments、Single-cell and spatial transcriptomics、Cancer Immunotherapy and Biomarkers

Predictive biomarkers for immune checkpoint inhibitors (ICIs) are largely identified retrospectively, but their prospective clinical utility remains unproven. Here, we report DUTRENEO, a prospective randomized phase 2 trial testing whether a retrospectively validated 18-gene bulk tumor inflammation signature (TIS) can guide neoadjuvant ICI therapy in muscle-invasive bladder cancer. The trial does not meet its primary endpoint, and this demonstrates that bulk gene-expression stratification does not sufficiently enrich for responders. To define the biology underlying this failure, we generate single-cell spatial transcriptomic profiles of 377 genes in ∼5.4 million cells across large tissue areas. Response is governed by spatial architectures invisible to bulk assays, including CD8 + T cell proximity to cancer cells, localized checkpoint co-expression within epithelial cancer-rich neighborhoods, and fibroblast-rich immune-excluded communities in non-responders. We provide a quantitative framework showing that ≥77 genes and ≥3-mm tissue diameter regions preserve predictive spatial signal at scalable throughput. The registration details of the trial are EudraCT 2017-002246-68.