The high heterogeneity within the tumor microenvironment (TME) represents a critical barrier limiting the efficacy of combination immunotherapy for primary liver cancer. The development of spatial single-cell proteomics compensates for the limitations of low throughput in traditional pathology and the loss of spatial information in single-cell sequencing. This technology enables high-throughput, in situ analysis of key proteins while maintaining tissue architectural integrity. Here, we review the progress of mainstream fluorescence- and mass spectrometry-based spatial imaging technologies in hepatobiliary tumors. We focus on elucidating key findings on TME architecture, such as the identification of immune-excluded stromal barriers and immunosuppressive “cellular neighborhoods”, the remodeling of spatial phenotypes by driver mutations, and the spatial evolution of the microenvironment during drug resistance and recurrence. Collectively, these technologies provide spatial evidence that deepens our understanding of hepatobiliary tumor development and progression, facilitating the discovery of predictive spatial biomarkers and the refinement of precision treatment strategies.