Cross-Modal Contrastive Learning for the Retrieval of Immunotherapy-Associated Molecular Signatures from Histopathology

Sigrid Vila-Bagaria, Mar Teixidó, Miquel Piñol, Felip Vilardell, Robert Montal +1

Gastric Adenocarcinoma is a leading cause of cancer mortality. Although "Inflamed/Non-Inflamed" subtypes have been proposed to predict immunotherapy response, their identification relies on a costly 10-gene RNA signature. We propose a Cross-modal Contrastive Multiple Instance Learning (CCMIL) framework for cross-modal retrieval, imputing these molecular signatures directly from standard Hematoxylin & Eosin (H&E) slides. By leveraging a supervised contrastive objective, CCMIL aligns visual morphological patterns with molecular phenotypes into a shared latent space. This establishes an interpretable search-by-case retrieval engine, enabling pathologists to query a whole slide image to surface transcriptomically coherent neighbors and approximate RNA signatures without genomic sequencing at inference. Our results demonstrate that this retrieval-first approach captures the continuous phenotypic spectrum of tumor inflammation and yields clinically interpretable attention heatmaps. Furthermore, the learned representation also supports competitive downstream classification, providing a practical molecular pre-screening strategy.