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

Table 2 Comparison of immunomodulatory and clinical-technical properties among radiofrequency ablation, microwave ablation, and cryoablation

Comparison parameter		RFA	MWA	Cryoablation	Putative mechanisms and clinical implications
Immunological parameter	Primary damage-associated molecular pattern release	HMGB1, heat shock proteins	HMGB1, ATP	HMGB1, ATP, CALR[23,33] (possibly a broader spectrum)	The freezing process better preserves antigens and facilitates the in situ exposure of “eat-me” signals like CALR[30]
	Antigen preservation integrity	Moderate/high (high temperature may denature some epitopes)	Moderate (rapid high temperature may alter antigen conformation)	High (low temperature better maintains native antigen conformation[25,70]	More intact antigens may help elicit high-affinity T-cell responses
	T-cell infiltration trend	Can increase, but may coincide with substantial Treg recruitment	Can increase, with heterogeneous effects	Significant increase in CD8+ T cells, some studies show Treg reduction[25,37]	May be related to a more favorable cytokine/chemokine profile
	Immune checkpoint induction	Induces PD-L1 upregulation	Induces PD-L1 upregulation	Potently induces PD-L1 upregulation[54,58]	Provides a clear target for combination with immune checkpoint inhibitors, but also suggests limited efficacy as monotherapy
	Risk to adjacent vasculature/bile ducts	High (thermal injury)	High (thermal injury)	Low (less affected by “heat sink” effect, collagen structure preserved)[24,76]	Makes cryoablation more suitable for tumors in high-risk locations, allowing more aggressive ablation for antigen release[80,81]
	Reported clinical abscopal effect	Case reports[65]	Rare	Relatively more preclinical evidence[28,38] and case reports[82,83]	Suggests its potential for inducing systemic immunity might be more pronounced
Technical and clinical parameters	Local efficacy for large tumors (> 3-4 cm)	Limited by “heat sink” effect	Generally more effective, less susceptible to “heat sink” effect[76,77]	Technically challenging; ice ball growth constrained by perfusion, leading to less predictable margins[76,77]	Durable local control is the prerequisite for any immune benefit. MWA may offer advantages in ablating large volumes
	Comparative LTP rate	Baseline standard, variable	Often comparable or superior to RFA in studies	Some studies suggest a potentially higher LTP rate, though data are inconsistent and influenced by learning curve[78,79]	Highlights the critical importance of operator expertise and optimal technique in cryoablation for foundational oncologic outcomes
	Technical complexity and cost	Relatively simple, lower cost	Moderately complex, intermediate cost	More complex and costly; requires specialized gas systems and often multi-probe setups[21,22]	Influences the learning curve and may limit widespread availability in resource-constrained settings

It summarizes key comparative findings from preclinical studies; clinical validation of these observations is ongoing. Representative references are indicated by superscript numbers. Risk assessments (low/high) denote the relative probability of major complications. The “putative mechanisms” column integrates hypotheses from the cited literature to explain the differences observed. When used in this table and the text, the terms “M1/M2” or “M2-like” serve as simplified descriptive shorthand for pro-inflammatory/anti-tumor and immunosuppressive/pro-tumor functional states, respectively. It is acknowledged that macrophage phenotypes in vivo are heterogeneous, plastic, and context-dependent. ATP: Adenosine triphosphate; CALR: Calreticulin; HMGB1: High mobility group box 1; LTP: Local tumor progression; MWA: Microwave ablation; PD-L1: Programmed death-ligand 1; RFA: Radiofrequency ablation; Treg: Regulatory T cell.