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The Landscape of Single-Cell Foundation Models: Design Principles, Applications, and Open Challenges

Shiyu Jiang, Zhaoyu Fang, Yujie Zhang, Xuting Zhang, Jérémie Kalfon, Weixu Wang, Xi Fu, Aakash Patel, Syed Rizvi, Yuancheng Ryan Lu, Siyu He, Yixin Wang, Kejun Ying, Peter Pao-Huang, Yifan Lu, Weize Xu, Mengchen Wang, Ziyang Miao, Jianhui Lin, Zitong Jerry Wang, Wei Ouyang, Tianlong Chen, Guoxian Yu, Min Li, Jiayi Ma, Fei Wang, Yuying Xie, Jiliang Tang, Raul Rabadan, David van Dijk, Pengtao Xie, Peng He, Emily B Fox, Le Song, Fabian J Theis, Eric Xing, Christina V Theodoris, Xiaojie Qiu+, Jiayuan Ding+.

Preprints 2026

Abstract

Recent advances in large-scale single-cell atlases and large language models (LLMs) have enabled the emergence of single-cell foundation models (scFMs), pretrained models that aim to learn transferable representations of cellular states across tissues, conditions, and molecular modalities. These models hold promise for moving single-cell analysis beyond task-specific pipelines towards unified, generalizable and predictive frameworks, yet their biological fidelity, generalization and scaling capacity, as well as utility for perturbation modeling remain challenging. In this review, we summarize recent progress in scFMs across key design dimensions, including data representation, model architecture and learning objective, and examine how these frameworks are being applied to biological discovery. We further critically assess current challenges and opportunities from multimodal pretraining atlas, emerging pretraining paradigms, downstream applications, and real-world barriers. This review provides a structured guide for both computational scientists and experimental biologists seeking to understand, develop, and apply foundation models for single-cell research.