arXiv:2611.13649v1 Announce Type: new Abstract: Predicting gene expression directly from hematoxylin and eosin (H&E) images offers a scalable and cost-effective approach to deriving spatial molecular insights from routine histology. Pathology foundation models, typically pretrained using tile-level objectives, may not adequately capture the fine-grained cellular features required for single-cell molecular prediction. In this work, we systematically evaluate and establish domain-informed and task-specific strategies for adapting pathology foundation models to single-cell spatial gene expression prediction. Using paired H&E and Xenium 5K data, our approach improves mean gene-wise Pearson correlation by 2.67x over the standard zero-shot baseline and achieves state-of-the-art performance on this task. We demonstrate strong gene-detection performance across the full gene panel (AUROC = 0.800) and importantly identify that predictive performance varies substantially across biological contexts, with our model achieving its highest Pearson correlation for spatially variable genes (r = 0.643). Our findings demonstrate that, despite the challenges of sparse single-cell measurements, H&E-derived representations can recover biologically meaningful spatial expression patterns, highlighting both the opportunities and limitations of morphology-based molecular inference at cellular resolution.