This valuable case series highlights the occurrence of Grade ≥ 3 irAEs in patients with low baseline serum IL‑6 who were treated with DT for HCC. Additionally, although the observation period and the number of cases were limited, we documented cases in which durvalumab could be rechallenged after successful management of irAEs, as well as a case where a single dose of DT alone achieved a sustained antitumor effect. The limited sample size posed challenges for conducting rigorous statistical analyses, which represents a limitation of the study. While the Mann–Whitney U test, supplemented by a Hodges-Lehmann estimation, provided statistically significant results, additional analyses using a previously reported IL-6 cut-off value (2.5 pg/mL) [5] showed that among patients with IL-6 < 2.5 pg/mL, three of four cases (75%) experienced Grade ≥ 3 irAEs, whereas only one of six cases (16.6%) was observed in the IL-6 ≥ 2.5 pg/mL group. However, Fisher’s exact test yielded a p value of 0.19, indicating no statistically significant difference, likely due to the small sample size and the resulting low statistical power. Nevertheless, this case series still allows for insightful and meaningful discussion.

In cancers other than HCC, particularly melanoma, research on biomarkers for irAEs is advancing, with a focus on cytokines [6]. Two studies have reported that lower baseline serum IL-6 levels were associated with the development of irAEs in melanoma patients treated with anti-CTLA-4 therapy. An analysis of baseline blood samples from 140 melanoma patients treated with anti-CTLA-4 therapy found that only low baseline IL-6 levels (< 2.5 ng/L) and female sex were correlated with an increased risk of Grade ≥ 3 irAEs after adjustment for follow-up time [5]. Similarly, lower levels of IL-6, IL-8, and sCD25 were associated with the development of anti-CTLA-4-induced colitis, as demonstrated using multiplex assays [7]. In patients with irAEs, a decreased frequency of regulatory T cells (Tregs) was observed, which was associated with more severe side effects and enhanced progression-free survival [8]. These findings suggest that patients with low baseline IL-6 levels may have a stable Treg population and a low-inflammatory, immunosuppressive environment. Anti-CTLA-4 therapy may disrupt Treg function, triggering immune dysregulation and increasing the risk of high-grade irAEs [9, 10]. Conversely, in HCC, high IL-6 levels have been reported as an unfavorable prognostic factor in patients treated with AB [11, 12]. More recently, IL-6 has also been reported as a prognostic factor in combination therapies such as radiotherapy and tislelizumab plus anlotinib [13]. Elevated CRP levels, which are closely linked to IL-6 activity, are also associated with poor prognosis in HCC, even during immunotherapy [14]. IL-6 is recognized as a major inducer of CRP and has been implicated in HCC progression [15]. IL-6 has been shown to promote tumor progression through the accumulation of myeloid-derived suppressor cells (MDSCs) [16]. Increased levels of MDSCs are associated with poor prognosis [17], and these cells can further enhance immunosuppressive pathways by inducing Tregs [18].

Taken together, these findings suggest that a low IL-6 environment may be characterized by reduced immunosuppressive cell activity, potentially allowing for enhanced antitumor responses during ICIs. However, such a state may also diminish the regulatory mechanisms that normally restrain immune overactivation, thereby increasing susceptibility to severe irAEs. Further research aiming to stratify patients based on this immunological “on–off” balance could facilitate safer and more effective implementation of immunotherapy in HCC.

From a clinical perspective, it is important to measure potential predictive and prognostic biomarkers such as IL-6 prior to administering DT. Comprehensive assessment of cardiac and pulmonary function, along with the patient's overall health status, is essential to evaluate their ability to tolerate potential severe irAEs.

In conclusion, low baseline IL-6 levels were significantly associated with the development of Grade ≥ 3 irAEs in HCC patients receiving DT therapy. However, appropriately managed severe irAEs may correlate with improved prognoses. Therefore, it is crucial to remain vigilant for irAEs both before and after initiating DT and to ensure early detection and prompt management.