Deciphering the Leading-Edge Spatiotemporal Microenvironment of Hepatocellular Carcinoma for Targeted Drug Discovery...

The leading-edge (LE) of hepatocellular carcinoma (HCC) is a critical region driving malignant progression and is closely associated with high patient mortality and marked intratumoral heterogeneity. Multi-omics integration identified elevated expression of SPARC and IGFBP7 in the LE region, which was associated with stromal remodeling-related transcriptional programs and an immune-depleted microenvironment. Cell-cell communication and pathway analyses further suggested potential links between LE-associated stromal states and pro-invasive signaling programs. Furthermore, we developed SpaPred, which demonstrated favorable performance in inferring the spatiotemporal heterogeneity of HCC at the spatial resolution. This model overcomes the limitations of existing algorithms in analyzing the composition of tissue spatial structures. Finally, integration of in silico trajectory-perturbation and pharmacogenomic drug-response analyses prioritized Oxaliplatin, Belinostat, and Temsirolimus as candidate compounds associated with LE-related transcriptional programs. These drug predictions are computational and require experimental validation. Collectively, SpaPred provides a hypothesis-generating framework for investigating spatial heterogeneity and candidate therapeutic vulnerabilities in HCC.