TRACE: Transcriptional Regulator Modulated Reference Geometry for Temporal Single-Cell Flow Matching

Progenitor-exhausted (Tpex) CD8${}^{+}$ T cells retain self-renewal and proliferative capacity, making their differentiation therapeutically important. Resolving this progression from temporal single-cell RNA sequencing is difficult because destructive sampling provides population snapshots without directly observed cell trajectories. Here, we introduce **TRACE**, a regulatory-informed conditional flow-matching model for predicting unobserved temporal populations. To incorporate regulatory direction into transport, we map temporal derivatives of expression-derived transcription-factor regulon activities into latent-space tangents for shape-preserving cubic-Hermite paths between optimal-transport-coupled populations. Across three T-cell exhaustion studies, the clearest improvements occurred at earlier holdouts. On the Gupta day 7 development holdout, $W_2$ was 21.7% lower than with linear CFM and 8.8% lower than with cubic CFM. Improvements extended to the earlier Giles and DSM holdouts, including a reduction in DSM day 8 $W_2$ from $11.175\pm 0.111$ with linear CFM to $10.725\pm 0.140$ with TRACE. At later holdouts, linear or alternative transport often matched or exceeded TRACE performance. These results support stage-dependent benefits of regulatory-informed reference paths for temporal interpolation, with the largest gains during earlier exhaustion-associated transitions.