Interleukin-6/interleukin-10 ratio and immune dysregulation after radiofrequency ablation

Abstract

BACKGROUND

The immune response following radiofrequency ablation (RFA) is characterized by a dynamic interaction between proinflammatory and anti-inflammatory factors. An elevated ratio of interleukin (IL)-6 to IL-10 may serve as a key indicator of post-RFA immune dysregulation.

AIM

To evaluate the prognostic relevance of the IL-6/IL-10 ratio as a surrogate indicator of immune dysregulation in patients with malignant liver tumors treated by RFA.

METHODS

We enrolled 91 patients undergoing RFA for hepatic malignancies were prospectively enrolled. Serum levels of IL-6 and IL-10 were measured both prior to the procedure and within 7 days post-RFA. Statistical analyses were conducted to assess the association between the IL-6/IL-10 ratio and clinical outcomes.

RESULTS

The study population consisted predominantly of males (74.73%), with a mean age of 60.88 ± 9.03 years. Most participants presented with ≤ 2 hepatic lesions (91.21%) and well-preserved hepatic function, as indicated by Child-Pugh class A status (98.9%). The mean lesion diameter was 26.27 ± 13.8 mm, and 78.02% had a documented history of hepatitis B virus infection. Post-procedural cytokine profiling revealed a marked and rapid surge in IL-6 concentrations peaking within 24 hours after RFA, whereas IL-10 exhibited only a modest elevation. Consequently, the IL-6/IL-10 ratio remained persistently elevated throughout the 7-day monitoring period (all P < 0.05). Multivariate logistic regression analysis identified the IL-6/IL-10 ratio as an independent prognostic indicator for adverse post-ablation outcomes (odds ratio = 1.11 per unit increment, 95%CI: 1.033-1.204, P = 0.006), with higher ratios signifying increased inflammatory burden. In contrast, elevated serum albumin levels conferred a protective effect (odds ratio = 0.81, 95%CI: 0.668-0.961, P = 0.021).

CONCLUSION

The IL-6/IL-10 ratio may constitute a clinically relevant biomarker indicative of immune dysregulation after RFA, with potential implications for understanding inflammation-driven outcomes and tailoring post-RFA management.

Key Words: Interleukin-6/interleukin-10 ratio; Immune dysregulation; Radiofrequency ablation; Hepatic malignancies; Inflammatory biomarkers

Core Tip: This study confirms that the post-procedural interleukin-6/interleukin-10 ratio serves as an independent prognostic biomarker for immune dysregulation in patients with malignant liver tumors following radiofrequency ablation. A persistently elevated ratio was significantly associated with adverse clinical outcomes, reflecting an immune imbalance dominated by a proinflammatory state. This highlights the clinical value of dynamic cytokine monitoring, with early postoperative measurements providing a practical tool for risk stratification. This metric can serve as a foundational parameter for developing comprehensive predictive models in the future, and its integration with clinical characteristics will advance the development of personalized management strategies after radiofrequency ablation.

INTRODUCTION

Radiofrequency ablation (RFA) has emerged as a minimally invasive therapeutic cornerstone for the management of hepatic malignancies, offering a favorable safety profile and clinical efficacy[1,2]. This technique utilizes localized high-frequency alternating current to generate thermal energy (50 °C-100 °C), inducing coagulative necrosis of target lesions while preserving surrounding healthy parenchyma through precise temperature control[3,4]. RFA for hepatic malignancies induces host immune activation via damage-associated molecular patterns (DAMPs), triggering a multifaceted immune response typified by a systemic dysregulation between proinflammatory and anti-inflammatory pathways[5]. This immune imbalance not only perturbs the functional dynamics of immune effector cells within the tumor microenvironment but also disrupts systemic immune homeostasis. The hepatic microenvironment presents unique immunological characteristics due to the dual role of the liver in metabolic regulation and immune surveillance, featuring high densities of Kupffer cells, innate-like lymphocytes, and tolerogenic dendritic cells, suggesting that post-RFA cytokine patterns may exhibit organ-specific features distinct from other ablation sites[6]. The inherently immunosuppressive milieu of malignant hepatic tumors and their associated microenvironment complicate the post-ablation immunological landscape. Such dynamic immune dysregulation profoundly impacts postoperative convalescence, tumor recurrence, and metastatic progression, constituting pivotal determinants for patient prognosis and therapeutic intervention strategies[7].

During RFA for hepatocellular carcinoma, the application of high-frequency alternating current via the electrode rapidly elevates the local tissue temperature to 60 °C-100 °C, inducing targeted coagulative necrosis[8]. This ablative process not only facilitates localized tumor cell destruction but also elicits a systemic inflammatory response, clinically manifested as post-ablation fever and other constitutional symptoms – collectively termed post-RFA syndrome[9].

Although post-RFA fever is predominantly a self-limiting, noninfectious inflammatory reaction, its clinical presentation often mimics infectious fever, potentially leading to diagnostic uncertainty. As a result, it may prompt unwarranted diagnostic interventions such as blood cultures, empirical antibiotic administration, and unnecessary prolongation of hospitalization. Reports indicate that up to 35% of patients undergoing RFA develop post-procedural fever[10], primarily attributable to sterile inflammation triggered by thermal injury rather than microbial infection[11]. Emerging evidence suggests that persistent febrile responses following RFA may correlate with early tumor recurrence[12].

Cytokines play a central role in regulating inflammation after ablation, particularly interleukin (IL)-6 and IL-10, which act as opposing forces in immunomodulation[13]. Previous studies have consistently documented a rapid and substantial increase in proinflammatory cytokines, particularly IL-6, peaking within hours to days post-ablation[14]. This surge is thought to be driven by the release of DAMPs from necrotic tumor cells and the activation of innate immune cells[15]. In contrast, the anti-inflammatory cytokine IL-10 often exhibits a more modest and delayed elevation, representing a counter-regulatory mechanism. This imbalance between pro-inflammatory and anti-inflammatory factors creates a state of transient immune dysregulation[16]. IL-6, released by macrophages, neutrophils, and tumor cells, drives inflammation by stimulating C-reactive protein production in the liver and shaping immune cell behavior through multiple signaling mechanisms, including Th17 cell development and suppressor cell activation[17]. In contrast, IL-10, mainly secreted by regulatory T cells and M2 macrophages, suppresses excessive immune reactions by blocking nuclear factor kappa B via signal transducer and activator of transcription 3 (STAT3), while also aiding tissue repair and blood vessel formation. The balance between these two cytokines, measured by the IL-6/IL-10 ratio, is now widely used to assess immune function in conditions like sepsis (predicting survival) and autoimmune diseases (linked to symptom severity), and postoperative recovery[18,19].

Our current understanding of post-RFA cytokine dynamics derives primarily from small studies examining individual cytokine levels at isolated time points. However, emerging paradigms in systems immunology emphasize the superior predictive value of cytokine ratios over isolated measurements, as they better capture the net inflammatory state and functional immune balance[20]. This conceptual framework finds strong support in recent multicenter investigations demonstrating the clinical relevance of IL-6/IL-10 imbalance in diverse conditions ranging from primary open-angle glaucoma (predicting progression) to major abdominal surgery (associated with complications)[21].

The present study was designed to address critical gaps in characterizing immune dysregulation following hepatic RFA[22]. Building upon preliminary observations of cytokine fluctuations, we systematically evaluated the temporal evolution of the IL-6/IL-10 ratio during the critical 7-day postoperative window[23]. Our investigation focused on three key aspects: (1) Quantifying the magnitude and duration of IL-6/IL-10 ratio elevation post-RFA; (2) Examining its correlation with established clinical parameters including lesion morphology and liver function indices; and (3) Assessing the predictive value of the ratio for post-procedural outcomes[24]. This research extended beyond descriptive cytokine profiling by incorporating comprehensive multivariate analyses to elucidate potential clinical applications of IL-6/IL-10 monitoring. Combining these biomarkers with standard clinical evaluations allows for a deeper analysis of immune reactions following ablation, which may help tailor individualized treatment approaches. This study specifically examined hepatocellular carcinoma patients with stable liver function (Child-Pugh A, comprising 98.9% of participants), creating a uniform group for preliminary biomarker testing and minimizing interference from severe liver impairment[22,25].

MATERIALS AND METHODS

Patient recruitment

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Harbin Medical University Cancer Hospital. Informed consent was obtained from all participants involved in the study. We prospectively enrolled patients with histopathologically confirmed hepatic malignancies scheduled to undergo RFA. Eligible participants were adults aged 18-80 years with diagnosed liver lesions. To reduce potential confounding variables, we excluded individuals with current infections, autoimmune conditions, or recent immunosuppressant therapy (Figure 1). All subjects gave written consent before joining the research. The investigation specifically targeted immune system changes occurring during the first week after RFA. Notably, nearly all participants (98.9%) had well-maintained liver function classified as Child-Pugh A, ensuring a consistent study population for analysis.

Figure 1 Flowchart of patient selection and enrollment with histopathologically confirmed hepatic malignancies undergoing radiofrequency ablation. HCC: Hepatocellular carcinoma; RFA: Radiofrequency ablation; TACE: Transarterial chemoembolization.

Ultrasound-guided percutaneous RFA

Prior to RFA, targeted liver biopsies were conducted in patients meeting established clinical criteria to ascertain definitive histopathological diagnosis. The ablation procedure was performed percutaneously using real-time ultrasound guidance. Patients were positioned supine, with two grounding pads attached to their thighs. Continuous monitoring of blood pressure and heart rate was maintained throughout the intervention. Following ultrasound localization of the puncture tract, conscious sedation was achieved using intravenous midazolam (0.075 mg/kg) and fentanyl (0.1 mg/kg). A cooled-tip RFA probe (17-gauge, Cool-tip system; Radionics, Burlington, MA, United States) was precisely advanced into the target lesion. Each ablation cycle lasted up to 12 minutes, with the electrode exposed tip length ranging from 2 cm to 3 cm. For lesions measuring ≤ 30 mm in maximal diameter, single-needle central placement sufficed, while larger tumors required overlapping ablations with dual-probe placement. Upon completion, the needle tract was cauterized during withdrawal to minimize bleeding risk. Post-procedural contrast-enhanced ultrasound was routinely performed to assess treatment adequacy. Residual tumor tissue was delineated by persistent enhancement within the ablation zone, necessitating immediate supplementary ablation until radiological confirmation of complete tumor eradication was achieved.

Demographic data collection and biospecimen handling

Comprehensive demographic and clinical data were meticulously collected from all enrolled participants, encompassing key variables such as age, sex, tumor burden, including lesion count and maximal diameter, and relevant medical history, particularly hepatitis B and C virus infection status. Peripheral blood specimens were systematically obtained preoperatively and serially within postoperative week 1 to quantitatively assess IL-6 and IL-10 levels via enzyme-linked immunosorbent assay. The datasets generated and analyzed are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request. To control for procedural heterogeneity, detailed clinical variables including the use of artificial ascites during RFA and the presence of spontaneous ascites were rigorously documented. A stringent, standardized protocol for specimen collection and processing was implemented throughout the study to mitigate preanalytical variability and preserve the fidelity of biomarker quantification.

Statistical analysis

The primary outcome, adverse post-RFA outcome, was a composite endpoint defined as the occurrence of any of the following within the 7-day postoperative period: (1) Persistent fever (≥ 38.5 °C for > 48 hours) requiring medical intervention; (2) Post-ablation syndrome of moderate-to-severe grade necessitating extended hospitalization; and (3) Other major inflammatory complications (e.g., systemic inflammatory response syndrome).

We conducted all statistical analyses with R software version 4.3.3. Numerical data, such as cytokine concentration and tumor size, appear as mean ± SD. For categorical measures like sex and Child-Pugh classification, we report counts and percentages. We computed the IL-6/IL-10 ratio at every observation time and examined its progression patterns. To determine how this ratio related to treatment outcomes, we ran multivariable logistic regression analyses that accounted for confounding variables like albumin and aspartate aminotransferase (AST) levels in blood tests. The predictive power of these models was verified through likelihood ratio testing, considering results statistically significant when P values fell below 0.05. We also created graphical plots to illustrate how inflammatory markers changed after the ablation procedure.

RESULTS

Patient characteristics

A total of 91 patients who underwent RFA for liver lesions were included. The cohort consisted predominantly of males (74.73%, n = 68), with a mean age of 60.88 ± 9.03 years. The majority of patients (91.21%, n = 83) presented with ≤ 2 lesions, while only 8.79% (n = 8) had > 2 lesions. The mean maximum lesion diameter was 26.27 ± 13.8 mm, indicating a heterogeneous distribution in tumor size. Regarding viral hepatitis history, hepatitis B was the most prevalent (78.02%, n = 71), followed by hepatitis C (8.79%, n = 8), while 13.19% (n = 12) of patients had no history of viral hepatitis. The use of artificial ascites during the procedure was reported in 27.47% (n = 25) of cases, whereas spontaneous ascites was observed in 9.89% (n = 9). Nearly all patients (98.9%, n = 90) were classified as Child-Pugh grade A, reflecting a well-preserved liver function in the study population (Table 1). These baseline characteristics suggest that the cohort was representative of a typical RFA-treated population, with a predominance of early-stage liver disease and low comorbidity burden. The demographic and clinical profiles provide essential context for interpreting the subsequent cytokine analyses.

Table 1 Demographic and clinical characteristics of patients undergoing radiofrequency ablation, n (%)/mean ± SD.

Variable	Groups	All patients
Age (years)		60.879 ± 9.03
Gender	Male	68 (74.73)
	Female	23 (25.27)
Number of lesions	≤ 2	83 (91.21)
	> 2	8 (8.79)
Maximum diameter of lesions (mm)	Hepatitis A	26.27 ± 13.80
Hepatitis virus history	Hepatitis B	71 (78.02)
	Hepatitis C	8 (8.79)
	No	12 (13.19)
Artificial ascites	Yes	25 (27.47)
	No	66 (72.53)
Ascites	Yes	9 (9.89)
	No	82 (90.11)
Child-Pugh grade	A	90 (98.90)
	B	1 (1.10)

IL-6/IL-10 ratio and clinical correlations

The longitudinal analysis of serum cytokine profiles revealed significant alterations in inflammatory markers following RFA. IL-6 levels exhibited a rapid and substantial increase during the early post-RFA phase, with a peak elevation observed within the first 24 hours (median increase of 4.8-fold compared to baseline) (P < 0.001; Figure 2A). In contrast, IL-10 levels displayed a more modest elevation pattern, with a 2.3-fold increase from baseline (P < 0.001; Figure 2B). During this process, a pronounced and sustained elevation of the IL-6/IL-10 ratio was observed (mean ratio 3.7 ± 1.2, P < 0.001 at all-time points compared to baseline; Figure 2C), indicating a persistent proinflammatory state following RFA. This shift in balance was likely driven by the disproportionate surge in IL-6 relative to the more moderate elevation in IL-10.

Figure 2 Temporal changes in serum interleukin-6 and interleukin-10 levels before and after radiofrequency ablation. A: Serum interleukin (IL)-6 levels significantly increased after radiofrequency ablation (RFA), peaking early post-treatment; B: Serum IL-10 levels showed a moderate increase following RFA; C: IL-6/IL-10 ratio was markedly elevated throughout the post-RFA period. IL: Interleukin.

The initial univariate analysis of immunological variables in relation to clinical outcomes (Table 2) revealed several statistically significant associations, with the most salient finding being that progressive increases in the IL-6/IL-10 ratio consistently correlated with post-RFA inflammatory manifestations, such as fever. Each unit increment in this cytokine ratio was associated with a 9% heightened risk of developing inflammatory complications [odds ratio (OR) = 1.09; 95%CI: 1.02-1.17; P = 0.01].

Table 2 Univariate logistic regression analysis of post-radiofrequency ablation inflammatory markers and clinical parameters.

Factor	Odds ratio	95%CI	P value
IL-6/IL-10 ratio	1.09	1.02-1.17	0.01
Albumin (G/L)	0.86	0.74-0.99	0.046
Aspartate aminotransferase (IU/L)	1.00	1.00-1.01	0.017

IL: Interleukin.

Serum albumin demonstrated a significant protective effect against post-procedural inflammation. Specifically, each unit increase in albumin level was associated with a 14% reduction in inflammatory risk (OR = 0.86, 95%CI: 0.74-0.99, P = 0.046), underscoring its potential immunomodulatory role and its capacity to maintain oncotic pressure during physiological stress. In contrast, elevated levels of AST were modestly but significantly associated with increased inflammatory risk (OR = 1.00, 95%CI: 1.00-1.01, P = 0.017), suggesting that impaired liver function may exacerbate immune activation following RFA. These observations highlight the complex interaction between conventional biochemical markers and cytokine signaling in shaping post-RFA inflammatory trajectories, with the IL-6/IL-10 ratio emerging as a particularly sensitive and reliable indicator of immune imbalance.

Multivariate logistic regression analysis (Table 3) further delineated the independent prognostic value of inflammatory markers after adjustment for potential confounders. The model exhibited strong predictive capacity (χ² = 20.92, P < 0.001), with the IL-6/IL-10 ratio remaining a significant independent predictor of adverse outcomes (OR = 1.11 per unit increase, 95%CI: 1.033-1.204, P = 0.006), reinforcing its role in identifying post-RFA immune dysregulation. This association remained robust even after adjusting for hepatic function indicators: Serum albumin preserved its inverse relationship with inflammatory risk (OR = 0.81, 95%CI: 0.668-0.961, P = 0.020), while AST levels continued to show a modest yet significant positive association (OR = 1.004, 95%CI: 1.002-1.007, P = 0.002). These findings suggest that although the IL-6/IL-10 ratio captures the net immunological imbalance, conventional liver function markers provide complementary prognostic insight. The model intercept (OR = 28.49, 95%CI: 0.08-3.66, P = 0.268) reflected a substantial baseline risk within the studied cohort, though it did not reach statistical significance.

Table 3 Multivariate logistic regression analysis of post-radiofrequency ablation inflammatory markers and clinical parameters.

Factor	β value	Odds ratio	95%CI	P value
Intercept value	3.35	28.49	0.08-3.66	0.268
IL-6/IL-10 ratio	0.11	1.11	1.033-1.204	0.006
Albumin (G/L)	-0.21	0.81	0.668-0.961	0.020
Aspartate aminotransferase (IU/L)	0.004	1.004	1.002-1.007	0.002

IL: Interleukin.

To further evaluate its discriminative capacity, receiver operating characteristic curve analysis was conducted. The IL-6/IL-10 ratio exhibited strong predictive performance, yielding an area under the receiver operating characteristic curve of 0.822 (95%CI: 0.7052-0.9387) (Figure 3). At the optimal threshold of 0.234, the model achieved an overall classification accuracy of 81.3%, with a sensitivity of 76.5% and specificity of 82.4%. These findings highlight the IL-6/IL-10 ratio as a reliable and independent biomarker for identifying patients at risk of immune dysregulation following RFA.

Figure 3 Receiver operating characteristic curve evaluating the predictive performance of the interleukin-6/interleukin-10 ratio for immune dysregulation following radiofrequency ablation. AUC: Area under the receiver operating characteristic curve.

DISCUSSION

RFA has emerged as a pivotal minimally invasive modality for the treatment of hepatic malignancies[26], owing to its capacity to induce targeted tumor cell necrosis via localized thermal injury and concurrently stimulate immune activation within the peritumoral microenvironment[27]. The complex alterations in the postoperative immune environment play a pivotal role in patient recovery and the development of complications. As key representatives of proinflammatory and anti-inflammatory cytokines respectively, IL-6 and IL-10, and particularly their ratio, have been widely utilized as indicators of systemic inflammatory balance and immune status. Extensive research has highlighted the relevance of the IL-6/IL-10 ratio in contexts such as tumor immunotherapy[28], regulation of inflammation[29], muscle regeneration[30], and neuroimmune interactions[31]. However, the temporal dynamics of this ratio following RFA, and its potential association with post-ablation immune dysregulation and clinical prognosis, remain largely unexplored.

Several studies have demonstrated that IL-6 levels significantly increase following RFA, reflecting the activation of acute inflammatory responses, whereas IL-10 levels remain relatively stable or show only mild elevation, indicating an anti-inflammatory regulatory effect. An elevated IL-6/IL-10 ratio signifies a sustained proinflammatory milieu post-procedure, which is closely associated with delayed recovery, inflammatory complications, and long-term prognosis.

In this study, we systematically analyzed the dynamic changes of the IL-6/IL-10 ratio in patients with hepatic malignancies undergoing RFA. We focused on the first 7 days postoperatively, a period known for peak cytokine perturbations, and observed a persistent increase in IL-6 levels alongside a modest rise in IL-10, resulting in a consistently elevated IL-6/IL-10 ratio. This cytokine imbalance indicates a predominant pro-inflammatory state post-RFA, which correlates with delayed recovery and inflammation-related complications. Multivariate analysis further confirmed the IL-6/IL-10 ratio as an independent predictor of postoperative immune dysregulation.

This study also identified a protective association between higher serum albumin levels and reduced inflammatory risk following RFA, with each 1 g/dL increase corresponding to an approximately 19% decrease in inflammation risk (OR = 0.81, 95%CI: 0.668-0.961, P = 0.021). This relationship likely reflects the multifaceted roles of albumin in maintaining vascular integrity, binding proinflammatory mediators, and modulating immune cell function[32,33]. Conversely, elevated AST levels (≥ 80 IU/L) were significantly associated with increased inflammatory risk (OR = 1.004, 95%CI: 1.002-1.007, P = 0.002), suggesting that hepatic dysfunction contributes to immune imbalance via impaired cytokine clearance or enhanced release of DAMPs. Although 98.9% of patients in this cohort were classified as Child-Pugh A, minimizing confounding from severe hepatic impairment, this homogeneity may limit the generalizability of the findings to populations with more advanced liver dysfunction.

These findings are consistent with previous studies demonstrating the utility of the IL-6/IL-10 ratio in identifying immune dysfunction. Notably, the temporal cytokine patterns observed in our cohort closely resemble those seen in sterile inflammatory responses to thermal injury, although the magnitude and duration of cytokine elevation appear more pronounced compared to other ablation modalities[14]. Our study extends this understanding by indicating that RFA not only induces an acute inflammatory response but also provokes prolonged systemic immune dysregulation. Mechanistically, IL-6 may amplify the inflammatory cascade through activation of downstream signaling pathways such as STAT3, while the compensatory upregulation of IL-10 appears insufficient to effectively counterbalance this excessive inflammation. The unique hepatic immune microenvironment, characterized by the presence of Kupffer cells and tolerogenic dendritic cells, may exert specific modulatory effects on postoperative cytokine dynamics.

This study was designed to validate the independent predictive value of the IL-6/IL-10 ratio during the acute phase following RFA. Consequently, the initial multivariate model primarily incorporated core indicators most directly associated with systemic inflammatory response and liver function (albumin and AST). It should be noted that factors such as tumor burden (size, number) and specific etiology (hepatitis B infection status) may also influence the immune response. Owing to constraints in the study timeline and follow-up duration, it was not feasible to systematically retrieve and include all potential evaluation metrics for unified analysis at this stage. Within the framework of this study, these additional variables were not incorporated into the core model to maintain model parsimony and statistical power. This specific focus of the study design, however, precisely highlights a critical direction for future research. Subsequent studies utilizing larger cohorts should aim to construct comprehensive predictive models that integrate a wider array of clinicopathological features. This approach will facilitate more precise identification of high-risk patients and elucidate the interactions between immunological markers and conventional tumor parameters. From a clinical translation perspective, a simplified model reliant on easily obtainable blood biomarkers (such as the IL-6/IL-10 ratio and albumin) may offer greater operational feasibility and potential for widespread adoption.

Another significant finding of this study is the consistent association observed between the IL-6/IL-10 ratio and post-procedural immune dysregulation across patients of different ages. Supplementary analysis revealed no significant interaction effect of age. Nevertheless, it is crucial to recognize the potential impact of immunosenescence and inflammaging as fundamental background factors influencing immune homeostasis. The acute inflammatory response observed in this study is likely shaped by a baseline immune state already modulated by age-related changes. Given the concentrated age distribution of our study population, future investigations specifically involving cohorts with a broader age range, particularly including more elderly patients, are warranted. Such studies should longitudinally track the entire process from acute inflammation to long-term immune reconstitution post-RFA to clarify the profound implications of immunosenescence on immune outcomes following local tumor therapy.

RFA exerts not only direct cytotoxic effects on tumor tissues but also orchestrates potent systemic antitumor immune responses through diverse immunomodulatory mechanisms. It augments both innate and adaptive immunity by activating critical effector populations such as natural killer cells and cytotoxic CD8⁺ T lymphocytes[34,35]. The thermal insult inflicted by RFA induces robust upregulation and extracellular release of heat shock protein-70, which in turn facilitates dendritic cell maturation and enhances antigen presentation, thereby amplifying antigen-specific T cell-mediated immune responses[36].

Concomitantly, RFA provokes a substantial surge in proinflammatory cytokines, including IL-1, IL-6, IL-8, and tumor necrosis factor-alpha, in the systemic circulation, indicative of a pronounced immune activation state[37]. RFA appears to attenuate tumor-induced immunosuppression by skewing the immune milieu toward a Th1-dominant profile, elevating the Th1/Th2 ratio, and reducing soluble IL-2 receptor levels, thereby contributing to an immunologically favorable tumor microenvironment[38]. The correlation between a high IL-6/IL-10 ratio and adverse outcomes likely extends beyond mere inflammation. Mechanistically, sustained IL-6 signaling via the STAT3 pathway may foster a protumorigenic microenvironment by promoting suppressor cell activity and inhibiting cytotoxic T-cell responses, thereby hampering effective antitumor immunity post-ablation. The insufficient compensatory IL-10 response fails to counterbalance these effects adequately.

Importantly, RFA-induced architectural alterations, such as the development of central necrotic cores and transitional zones, are intricately associated with heightened heat shock protein expression and localized infiltration of immune effector cells, underscoring the pivotal role of tissue remodeling in initiating and sustaining antitumor immunity[39-43].

Nevertheless, it remains to be elucidated whether the postoperative elevation of the IL-6/IL-10 ratio predominantly reflects sterile inflammation secondary to thermal damage or represents a more complex immune reprogramming within the tumor microenvironment. Given the dual capacity of RFA to induce tumor cell death and modulate immune cell trafficking and cytokine dynamics in peritumoral regions, the observed immunological shifts likely result from an intricate interaction between local tissue injury and systemic immune recalibration. Future investigations incorporating spatially resolved cytokine mapping and in-depth phenotypic profiling of tumor-infiltrating immune subsets at preoperative, intraoperative, and postoperative intervals are warranted to delineate the precise origin and functional significance of these immune alterations.

From a clinical perspective, real-time monitoring of the IL-6/IL-10 ratio offers a practical and effective approach for early detection of postoperative immune dysregulation, facilitating timely adjustments in immunomodulatory interventions. Stratifying patients based on cytokine profiling enables personalized therapeutic strategies, such as the early administration of IL-6 inhibitors or IL-10 agonists, aimed at restoring immune homeostasis and enhancing postoperative recovery[44,45].

Despite these important insights, several limitations warrant consideration. The single-center design and small sample size (n = 91) may limit the external validity of the results and preclude subgroup analyses based on tumor characteristics or ablation parameters[46,47]. From a clinical translation perspective, our post hoc analysis suggests that a single measurement at 24 hours post-RFA has substantial predictive value, which would be far more feasible than serial measurements in routine practice. Future research should focus on validating a specific cut-off value at this early timepoint to guide potential interventions. The 7-day follow-up period, while sufficient to capture acute cytokine dynamics based on prior kinetic studies, precludes assessment of long-term immune recovery patterns or clinically relevant endpoints such as tumor recurrence (typically evaluated at 3-6-month intervals) or overall survival[48]. The lack of standardized post-procedural anti-inflammatory protocols may have introduced variability in inflammatory responses, although this also reflects real-world practice[49]. Future multicenter studies with larger, more diverse cohorts (including Child-Pugh B/C patients) and extended follow-up (≥ 12 months) are needed to validate these findings and explore the therapeutic potential of modulating the IL-6/IL-10 balance through targeted interventions such as IL-6 receptor antagonists or IL-10 supplementation. Such research could further elucidate the relationship between early cytokine dynamics and late clinical outcomes, potentially paving the way for personalized post-RFA management strategies that optimize both safety and oncologic efficacy.

It is important to note that our study population was highly selected, consisting predominantly of patients with early-stage disease (≤ 2 lesions), well-preserved liver function (Child-Pugh A), and hepatitis B etiology. This homogeneity strengthens the internal validity for our preliminary hypothesis but necessarily limits the generalizability of our findings to patients with more advanced liver dysfunction or different etiologies. Future studies in broader populations are needed to validate these results.

The findings of this study provide substantive support to existing clinical evidence that monitoring cytokine ratios enables early identification of postoperative immune dysregulation, particularly in the context of locoregional tumor ablation where inflammatory responses critically influence both short-term recovery and long-term therapeutic outcomes. The robustness and consistency of these results across the patient cohort underscore the potential of integrating immunological profiling into routine postoperative surveillance protocols, thereby facilitating more precise identification of high-risk individuals and enabling prompt implementation of targeted interventions.

CONCLUSION

This study highlights the IL-6/IL-10 ratio as a key biomarker for post-RFA immune dysregulation, with elevated IL-6 and a sustained high ratio predicting poorer outcomes (OR = 1.11, P = 0.006). Serum albumin showed a protective effect (OR = 0.81, P = 0.021), while higher AST levels increased inflammatory risk (OR = 1.004, P = 0.002). Despite insights into acute cytokine shifts, the single-center design and short follow-up necessitate further validation. The ratio may aid in monitoring post-RFA inflammation and guiding clinical management.

ACKNOWLEDGEMENTS

We would like to thank the team from Harbin Medical University for their expert assistance in data analysis.