Can Protein-Derived Knowledge Improve Pathology Foundation Models?

Abstract

Molecularly guided pathology foundation models (PFMs) exploit transcriptomic or proteomic information to enrich whole-slide image (WSI) representations, yet effectively leveraging large standalone molecular corpora remains challenging. First, existing molecular foundation models encode protein sequences or single-cell states, not the patient-level bulk expression profiles paired with WSIs. Second, because cross-modal supervision is restricted to paired WSI-omics samples, knowledge from standalone molecular corpora reaches the pathology encoder only indirectly, creating a paired-support bottleneck. To address these challenges, we propose a three-stage framework that decouples proteomic knowledge acquisition from cross-modal transfer, yielding ProSlide, a slide-level hierarchical pathology foundation model. First, to close the modality gap, we pretrain a Proteomic Foundation Encoder (PFE) on 12,695 sample-level bulk protein profiles using virtual profile generation and expression-space multi-view pretraining. Second, we pretrain ProSlide, a patch-region-slide encoder, to predict protein expression from paired WSI-protein samples. Third, to relax the paired-support bottleneck, we introduce Prot2Path, a cross-modal relational distillation objective. For each paired sample, it aligns the similarity distributions of the WSI and its protein profile over a shared, frozen bank of PFE-encoded paired and standalone profiles. We evaluate ProSlide on 12 downstream tasks across breast, lung, and renal cancers. Despite being pretrained with only 2,229 WSIs and 12,695 sample-level protein profiles, ProSlide achieves the highest mean accuracy and AUC within each cancer group.