The convergent thread across this cluster is the deconstruction of hepatocellular carcinoma and hepatoblastoma heterogeneity through single-cell and spatial technologies, aimed at resolving how tumor cells, cancer-associated fibroblasts, and myeloid populations cooperate to build an immunosuppressive microenvironment. Single-cell RNA sequencing repeatedly emerges as the enabling technology—unveiling cancer heterogeneity, mapping functional cell subsets, identifying molecular drivers, and revealing phenotypic landscapes—all of which feed forward into the development of prognostic tools and targeted therapies. This reflects a field-wide shift from bulk molecular characterization toward cellular-resolution dissection of the tumor microenvironment, where extracellular matrix, cancer-associated fibroblasts, tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells are positioned as active co-conspirators in immune evasion rather than passive bystanders.
A second major axis is metabolic-immune crosstalk as a driver of tumor progression and immunotherapy resistance. HKDC1 exemplifies this: induced by hypoxia, it stabilizes β-catenin via glycogen synthase kinase 3β binding to enhance cancer stemness, with stronger prometastatic association than related hexokinases HK1/HK2, validated in organoid and mouse models. Parallel to this, lactate—a byproduct of reprogrammed tumor metabolism—drives lactylation-based epithelial-mesenchymal transition and reshapes nutrient competition within the microenvironment, while dysregulated palmitoylation further links metabolic rewiring to oncogenic signaling. These metabolic mechanisms converge with immune evasion pathways (e.g., NPC1L1) and immunosuppressive networks (CD90+ CAFs via LAMA4, Annexin A2) to explain resistance to immune checkpoint blockade and anti-PD-1/PD-L1 therapy, motivating combination strategies that pair checkpoint inhibitors with metabolic or stromal-targeting agents.
Therapeutically, the report captures a trend toward engineered, tumor-targeted immunogenic cell death platforms—sonodynamic therapy, CD44-targeted hyaluronic acid nano-prodrugs co-delivered with anti-PD-L1—designed to convert immunologically "cold" tumors into "hot" ones by triggering calreticulin exposure, HMGB1 release, and CD8+ T cell recruitment, including clearance of senescent cancer cells via cGAS-STING signaling. Concurrently, a diagnostic/biomarker trajectory is developing in parallel: exosome proteomic profiling, biosensor detection platforms, and intratumor microbiome signatures are being advanced as non-invasive biomarkers of disease progression and treatment response, positioning liquid biopsy approaches as companion tools to guide the same immunometabolic and immunotherapeutic strategies emerging from single-cell and mechanistic studies.
Together, these threads describe a maturing translational pipeline: single-cell-resolved discovery of immune-metabolic drivers → mechanistic validation in organoid/mouse models → engineered combination immunotherapies → biomarker-guided clinical deployment, all converging on overcoming immune evasion and immunotherapy resistance in liver cancer.