Harmonised benchmarking of foundation models for single-cell and spatial transcriptomics reveals context-dependent generalisation

Single-cell and spatial foundation models promise transferable biological representations, yet their generality remains largely untested across modalities, biological domains and analytical tasks.

We benchmarked six representative models, Nicheformer, CellPLM, scGPT-spatial, GenePT, scELMo and Novae, using a harmonised framework spanning scRNA-seq, spatial transcriptomics and Perturb-seq.

We evaluated zero-shot and continually pretrained clustering, supervised annotation, marker-gene concordance and perturbation prediction.

Model performance was strongly conditional: expression-trained cell-level transformers best resolved many cell-identity tasks, spatial and graph-aware models better preserved tissue architecture, and language-derived gene embeddings were competitive for selected perturbation-response metrics.

No model dominated across tasks, and rankings shifted with modality, preprocessing, tokenisation, biological prior, domain shift and metric choice.

This benchmark provides practical guidance for model selection and argues that future models should be judged by biological generalisation, interpretability and perturbation-grounded validity, not by scale or leaderboard performance alone.