Cryoablation remodels the immune microenvironment in hepatocellular carcinoma: From mechanistic insights to clinical translation in combination immunotherapy

Table 5 Summary of the multifactorial determinants influencing outcomes and the current translational hurdles for cryoablation combined with immunotherapy in hepatocellular carcinoma

Category	Core variable/challenge	Specific elements and impact	Clinical implication/optimization direction
Key efficacy variables	Technology-related variables[37,78,94,103-111]	Ablation mode and completeness: Contradiction between preclinical “incomplete ablation” for immune stimulation and clinical need for local control. Current consensus favors radiologically complete ablation when combined with effective systemic immunotherapy. Technical parameters: Probe layout, freezing rate, minimum temperature, and number of freeze-thaw cycles influence cell death mode, damage-associated molecular pattern release, and the intensity/quality of the immune response	Paradigm shift from “radical ablation” to “strategic immuno-ablation”. Standardize and optimize parameters to maximize the in situ vaccine effect and immune benefits
	Baseline host and tumor variables[103,112-117]	Host status: Systemic immune capacity, immunodeficiency, severity of background liver disease (Child-Pugh grade, albumin-bilirubin score), cirrhosis, and hepatitis B virus/hepatitis C virus infection status. Tumor features: Intrinsic immunogenicity (tumor mutational burden, neoantigen load), baseline immune cell infiltration level (immune score), programmed death-ligand 1 expression. Conventional metrics like tumor burden and alpha-fetoprotein levels also correlate with efficacy	Foundation for personalized therapy. Pre-identification of “advantaged populations” via molecular imaging or liquid biopsy is key. The combination may potentiate the conversion of “immune-cold” tumors
	Treatment strategy and dynamic monitoring variables[27,94,118]	Timing and sequence of combination: The sequence (neoadjuvant, concurrent, adjuvant) and interval are core points of controversy for strategy optimization. Management of immunosuppressive complications: Complications (e.g., massive pleural effusion, “cryoshock”) may induce systemic immunosuppression. Dynamic peripheral blood immune monitoring: Dynamic changes in lymphocyte subsets, neutrophil-to-lymphocyte ratio, T-cell receptor clonal expansion, and cytokine profiles serve as a real-time, non-invasive “liquid biopsy” window	Dynamic strategy adjustment based on baseline conditions. Active complication management to preserve efficacy. Utilize blood-based monitoring for early response assessment and efficacy prediction
Current major challenges	Lack of high-level prospective evidence[78,118,119]	Current evidence is primarily from retrospective analyses or small single-arm studies, limited by selection bias, confounding factors, and protocol heterogeneity. Conclusions are hypothesis-generating	Future phase III randomized controlled trials must employ prospective randomized design, stratified randomization, standardized protocols, and appropriate control arms (e.g., atezolizumab + bevacizumab) to confirm survival benefit
	Immunosuppressive risk and combination safety[118]	Ablation itself may stimulate immunosuppression. Overlapping toxicities (e.g., immune-related hepatitis vs post-ablation injury) require careful management. Significant heterogeneity exists in patient selection	Need for strategies to counteract ablation-induced immunosuppression and to differentiate/manage overlapping toxicities. Establishing universal patient selection criteria is difficult
	Evolution of efficacy evaluation standards[120]	Traditional size-based criteria (e.g., Response Evaluation Criteria in Solid Tumors) may fail to capture delayed responses or pseudoprogression induced by immunotherapy	Comprehensive evaluation incorporating functional imaging (e.g., contrast-enhanced magnetic resonance imaging, positron emission tomography) and immune-related response criteria is necessary