HiFi-ST: High-Fidelity Reconstruction of Continuous Spatial Transcriptomic Expression Fields via Conditional Neural Fields

Spatial transcriptomics characterizes tissue-scale gene expression patterns, yet its observations are sparse discrete samples of an underlying continuous molecular field, leading to spatial aliasing and sub-resolution information loss. Existing methods usually formulate this task as spot-level point regression, making it difficult to capture both expression continuity and the regional nature of observation. Here, we propose HiFi-ST, a conditional neural field framework for continuous spatial transcriptomics modeling. HiFi-ST formulates spatial gene expression prediction as continuous expression field learning, models each spot as a regional observation over a finite support domain, approximates local integration through Monte Carlo sampling, and integrates multiscale tissue feature extraction with FiLM-based conditional modulation to improve modeling of complex spatial heterogeneity and consistency with the underlying measurement process. Systematic evaluation on three independent datasets (HER2+, cSCC, and Alex_NatGen) showed that HiFi-ST outperformed mclSTExp, BLEEP, THItoGene, His2ST, and HisToGene on key metrics. On HER2+, HiFi-ST achieved an average PCC improvement of 65.1% and an average MSE reduction of 40.9%; on cSCC, PCC improved by 10.2% and MSE decreased by 51.2%; on Alex_NatGen, PCC improved by 80.0% and MSE decreased by 16.3%. In addition, the learned multiscale tissue representations supported downstream spatial immunoanalysis, including assisted identification of candidate TLS regions. Overall, HiFi-ST provides a unified framework bridging discrete measurements and continuous expression field reconstruction for tumor microenvironment analysis and spatial immune structure characterization.