Self-supervised vision models have achieved notable success in digital pathology. However, their domain-agnostic transformer architectures are not originally designed to account for fundamental biological elements of histopathology images, namely cells and their complex interactions. In this work, we hypothesize that a biologically-informed modeling of tissues as cell graphs offers a more efficient representation learning. Thus, we introduce GrapHist, a novel graph-based self-supervised learning framework for histopathology, which learns generalizable and structurally-informed embeddings that enable diverse downstream tasks. GrapHist integrates masked autoencoders and heterophilic graph neural networks that are explicitly designed to capture the heterogeneity of tumor microenvironments. We pre-train GrapHist on a large collection of 11 million cell graphs derived from breast tissues and evaluate its transferability across in- and out-of-domain benchmarks. Our results show that GrapHist achieves competitive performance compared to its vision-based counterparts in slide-, region-, and cell-level tasks, while requiring four times fewer parameters. It also drastically outperforms fully-supervised graph models on cancer subtyping tasks. Finally, we also release five graph-based digital pathology datasets used in our study at https://huggingface.co/ogutsevda/datasets , establishing the first large-scale graph benchmark in this field. Our code is available at https://github.com/ogutsevda/graphist .
@article{arxiv.2603.00143,
title = {GrapHist: Graph Self-Supervised Learning for Histopathology},
author = {Sevda Öğüt and Cédric Vincent-Cuaz and Natalia Dubljevic and Carlos Hurtado and Vaishnavi Subramanian and Pascal Frossard and Dorina Thanou},
journal= {arXiv preprint arXiv:2603.00143},
year = {2026}
}