The dominant trend emerging from this cluster is the convergence of locoregional/physical therapies—sonodynamic therapy, transarterial embolization, ablation, and nanoparticle-based drug delivery—with systemic immunotherapy to overcome the immunosuppressive hepatocellular carcinoma (HCC) microenvironment. Engineered nanoplatforms exemplified by Mn-GMSs (manganese-doped gelatin microspheres encapsulating MnWOx nanodots) illustrate this trajectory: they combine sonodynamic ROS generation under ultrasound irradiation with transarterial embolization to physically destroy tumors, while simultaneously releasing manganese ions that activate the cGAS/STING pathway in dendritic cells, driving their maturation and amplifying antitumor immunity. This immunogenic priming is then synergized with PD-L1 checkpoint blockade, validated across mouse, rat, and rabbit tumor models, establishing a template for "in situ vaccination" strategies that convert locally ablative treatments into systemic immune activators. Parallel work on ablation therapy more broadly reinforces this theme, showing its capacity to induce anti-tumor immune responses that synergize with immunotargeted therapy and interventional approaches, with nanotechnology poised to further refine precision and safety.
A second thread concerns natural/traditional compounds—Calculus bovis and related botanicals—acting through the Wnt/β-catenin pathway to reprogram the tumor immune microenvironment, specifically by suppressing M2 tumor-associated macrophage polarization. These agents are validated through in vitro and in vivo experiments and are positioned as potential components of comprehensive, multidisciplinary liver cancer treatment, reflecting growing interest in mechanistically-grounded natural products as adjuncts or immune-microenvironment modulators alongside conventional and nanomedicine-based approaches.
A third and increasingly prominent axis is precision immuno-oncology guided by molecular and sex-specific biomarkers. NOTCH1 expression emerges as a sex-chromosome-dependent determinant of immune checkpoint inhibitor efficacy, enhancing CD8+ T-cell-mediated antitumor responses and immunotherapy benefit in male patients, while paradoxically associating with immune escape, higher HCC incidence, and poor response in female patients. This finding underscores an emerging paradigm of patient stratification based on molecular and demographic variables to optimize immunotherapy selection, complementing biomarker discovery efforts (e.g., CD147, liver cancer-specific lncRNAs and proteins) aimed at refining prognosis and therapeutic decision-making.
Collectively, these threads point toward a future HCC treatment landscape built on multimodal, mechanistically rational combinations—nanomedicine-enabled locoregional immune priming, checkpoint blockade, natural-product immunomodulation, and biomarker-driven patient stratification—converging to address the persistent challenges of therapeutic resistance, systemic toxicity, and heterogeneous immunotherapy response that continue to limit outcomes in liver cancer.