Xia Lei

Despite advances in cancer therapies, treatment responses remain highly variable due to the complexity and heterogeneity of the tumor microenvironment. The tumor microenvironment comprises malignant, immune, stromal, and endothelial cells, along with extracellular matrix and soluble factors, all organized into spatially distinct communities that evolve dynamically throughout tumor progression and therapy. These spatial structures orchestrate tumor behavior, immune evasion, and drug resistance. Recent breakthroughs in spatial omics technologies, including spatial transcriptomics and spatial proteomics, have enabled high-resolution, multiplexed mapping of tissue architecture and molecular characteristics. These technologies provide valuable insights into how the spatial organization of cells and signaling networks within the tumor microenvironment influences therapeutic efficacy. Notably, specific structures, such as tertiary lymphoid structures, fibroblast-mediated stromal barriers, and vascular heterogeneity have been identified as spatial determinants of treatment response. By delineating cellular communities and their interactions, spatial omics technologies can reduce intratumoral complexity into clinically interpretable modules. This review summarizes the diversity of these spatial structures and their relationships with treatment outcomes in immunotherapy, chemotherapy, radiotherapy, and targeted therapy. In addition, it highlights present challenges in data integration, analytical standardization, and functional validation, and discusses future directions for incorporating spatial omics technologies into precision medicine.

Hepatocellular carcinoma (HCC) has become the fourth leading cause of cancer-related deaths worldwide; annually, approximately 830,000 deaths related to liver cancer are diagnosed globally. Since early-stage HCC is clinically asymptomatic, traditional treatment modalities, including surgical ablation, are usually not applicable or result in recurrence. Immunotherapy, particularly immune checkpoint blockade (ICB), provides new hope for cancer therapy; however, immune evasion mechanisms counteract its efficiency. In addition to viral exposure and alcohol addiction, nonalcoholic steatohepatitis (NASH) has become a major cause of HCC. Owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance, NASH-associated HCC patients respond much less efficiently to ICB treatment than do patients with other etiologies. In addition, abnormal inflammation contributes to NASH progression and NASH–HCC transition, as well as to HCC immune evasion. Therefore, uncovering the detailed mechanism governing how NASH-associated immune cells contribute to NASH progression would benefit HCC prevention and improve HCC immunotherapy efficiency. In the following review, we focused our attention on summarizing the current knowledge of the role of CD4⁺T cells in NASH and HCC progression, and discuss potential therapeutic strategies involving the targeting of CD4⁺T cells for the treatment of NASH and HCC.