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

Authors

Enrique Grande, Mustafa Sibai, Daniela Grases, Elena Andrada, Oscar 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, M Angel Climent, Mario Domínguez, Patricia Galván, Isabel Galante, Juan F García, Elena Perez, Xavier García Del Muro, Félix Guerrero-Ramos, Miriam Marqués, Pablo Maroto, Jesús M Paramio, Alvaro Pinto, Aleix Prat, Núria Malats, Ignacio Durán, Eduard Porta-Pardo, Francisco X Real

Published in

Cell reports. Medicine. Pages 102878. Jun 23, 2026. Epub Jun 23, 2026.

Abstract

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.

PMID:
42335902
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.

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