Hepatocellular carcinoma (HCC) is the predominant primary malignancy of the liver, accounting for approximately 75-85% of all liver cancers. Worldwide, HCC ranks as the sixth most prevalent malignancy and the fourth leading cause of cancer-related mortality (1). Owing to its typically asymptomatic progression, most patients are diagnosed at intermediate or advanced stages, thereby missing the opportunity for potentially curative surgical treatment and consequently facing an unfavorable prognosis.

For patients who are unsuitable candidates for curative therapy, transarterial chemoembolization (TACE) remains a standard and widely adopted locoregional treatment approach (2). By obstructing the tumor’s arterial blood supply and inducing localized ischemic necrosis, TACE can effectively suppress tumor progression. However, this procedure also leads to the development of a hypoxic tumor microenvironment, which upregulates vascular endothelial growth factor (VEGF) expression and consequently promotes tumor recurrence and metastasis (3). As a result, the therapeutic efficacy of TACE monotherapy for HCC remains unsatisfactory (4).

In recent years, the advent of targeted immunotherapies has profoundly reshaped the therapeutic paradigm for unresectable HCC (5, 6). Combination regimens, such as atezolizumab plus bevacizumab, have been established as the standard first-line treatment for advanced HCC. The large multicenter Chinese clinical trial ORIENT-32 demonstrated that sintilimab combined with a bevacizumab biosimilar achieved significantly greater efficacy than sorafenib, resulting in higher overall response rate (ORR) and prolonged progression-free survival (PFS) (7). Based on these results, the sintilimab-bevacizumab biosimilar combination has been endorsed in clinical guidelines as a first-line systemic therapy.

Although the systemic efficacy of sintilimab in combination with a bevacizumab biosimilar has been well established, research exploring its combination with TACE in patients with HCC are still relatively scarce. Therefore, the present study aimed to investigate the efficacy and safety of TACE combined with sintilimab and a bevacizumab biosimilar in patients with uHCC, thereby providing additional clinical evidence to support therapeutic decision-making.

This study evaluated the real-world efficacy and safety of TACE combined with sintilimab (a PD-1 inhibitor) and a bevacizumab biosimilar (an anti-VEGF agent) in 60 patients with unresectable HCC. The key findings revealed a median overall survival (mOS) of 24.0 months, median progression-free survival (mPFS) of 13.0 months, and an objective response rate (ORR) of 83.3% per mRECIST, along with a disease control rate (DCR) of 91.7%. These results demonstrate that the triple combination regimen offers promising efficacy and manageable safety, supporting its potential as a viable therapeutic strategy for patients with uHCC.

With the continuous evolution of HCC treatment paradigms, monotherapy has become increasingly insufficient to meet the clinical demand for prolonged survival and effective disease control (8, 9). In recent years, the integration of locoregional and systemic therapies has emerged as a promising approach to enhance clinical outcomes. In particular, the combination of immunotherapy with anti-angiogenic agents has shown synergistic antitumor activity. However, despite encouraging progress with various combination strategies, the overall prognosis for HCC patients remains suboptimal (10, 11). Therefore, further exploration of optimal combination regimens is warranted to improve therapeutic efficacy and extend survival.

For patients with HCC undergoing TACE monotherapy, the mPFS typically ranges from 7 to 8 months (12, 13). In contrast, combination therapies have demonstrated superior efficacy. The ORIENT-32 trial established sintilimab plus a bevacizumab biosimilar as a first-line regimen for uHCC, showing significantly improved mPFS compared with sorafenib (4.6 vs. 2.8 months; P < 0.0001), though mOS was not reached at the time of reporting (7). Similarly, the IMbrave150 trial reported a 5.8-month improvement in mOS with atezolizumab plus bevacizumab over sorafenib (14). More recently, the CHANCE2211 study demonstrated that TACE combined with camrelizumab and apatinib resulted in significantly longer mOS (24.1 vs. 15.7 months) and mPFS (13.5 vs. 7.7 months) compared with TACE alone (15). Likewise, the phase III LEAP-012 trial showed that TACE plus lenvatinib and pembrolizumab significantly prolonged mPFS versus TACE plus placebo (14.6 vs. 10.0 months; P = 0.0002), with an ORR of 71.3% per mRECIST (16). Consistently, the EMERALD-1 trial revealed that Durvalumab plus bevacizumab plus TACE significantly improved progression-free survival compared with TACE alone (15.0 months vs. 8.2 months; p=0.032) (17). In a nationwide, retrospective, cohort study (n=826), combination therapy (TACE plus PD-[L]1 blockades and molecular targeted treatments) not only improved OS, FPS and ORR more effectively than TACE monotherapy, but also was the most important predictive indicator for OS and PFS (18). These findings collectively highlight the therapeutic advantage of combining TACE with immunotherapy and targeted agents over conventional monotherapy, which has the potential to set a new standard of care.

In this study, we evaluated the therapeutic efficacy and safety of TACE combined with sintilimab and bevacizumab in patients with uHCC. The mOS of 24.0 months in our study was more favorable than that of TACE alone, which was 15.7-19.4 months (4, 18), demonstrating superior outcomes. The mPFS was 13.0 months, which was notably better than the 4.6 months observed in the sintilimab combined with bevacizumab treatment group in the ORIENT-32 study (7). Although our study demonstrated encouraging survival outcomes, these differences arise from indirect cross-study comparisons and are influenced by heterogeneity in patient characteristics, study design, and assessment methods; therefore, the findings should be interpreted with caution and require confirmation in prospective controlled studies. The favorable outcomes of TACE plus sintilimab and bevacizumab biosimilar stem from well-established synergistic mechanisms. First, TACE induces localized tumor ischemia and necrosis, releasing tumor-associated antigens and increasing the expression of PD-L1 in tumor cells, which activates tumor-specific immune response (19, 20). This “in situ vaccination” effect is amplified by sintilimab, which blocks PD-1-mediated immune checkpoint inhibition, restoring cytotoxic T-cell function against residual tumor cells (21, 22). Second, TACE upregulates VEGF expression in the hypoxic tumor microenvironment, promoting angiogenesis and immune suppression (e.g., recruitment of regulatory T cells) (3, 23). Bevacizumab counteracts this by inhibiting VEGF, normalizing tumor blood vessels to improve drug delivery and reduce immune suppression (24). Moreover, TACE may be associated with lower intratumoral levels of exhausted effector T cells (CD8⁺/PD-1⁺) and regulatory T cells (CD4⁺/FOXP3⁺), which have the potential to shift the tumor microenvironment from an immunosuppressive to an immune-supportive state and thereby enhance the therapeutic efficacy of PD-L1 inhibitors (24, 25). It should be noted that although VEGF inhibition is a key antitumor mechanism in combination therapy, it can also directly give rise to treatment-related adverse events such as proteinuria. Evidence indicates that these toxicities result from disruption of the physiological roles of VEGF in maintaining the integrity of the glomerular filtration barrier and vascular homeostasis, and thus can be considered manageable “on-target” effects (26, 27). Thus, the combination of TACE, sintilimab, and bevacizumab exhibits complementary mechanisms of action that collectively mitigate tumor progression and confer clinical benefits.

In terms of safety, treatment-related adverse events (tr-AEs) occurred in 93.3% of patients, with decreased platelet count (41.7%), proteinuria (35.0%), and elevated ALT/AST (33.3%) being the most common. Grade ≥ 3 tr-AEs were observed in 23.3% of patients, primarily comprising elevated transaminases. All tr-AEs were effectively managed through a proactive protocol: routine blood monitoring and timely use of platelet-boosting agents for thrombocytopenia; pre-cycle quantitative urine tests and dose adjustment/interruption of bevacizumab for proteinuria; and optimization of TACE embolization combined with hepatoprotective drugs for transaminitis. Crucially, all events were controllable via temporary drug withholding, dose modification, or symptomatic support, and no treatment-related deaths occurred. These findings are consistent with previous reports on TACE combined with immunotherapy and anti-angiogenic agents (15–17), indicating that the triple regimen is generally well-tolerated in clinical practice.

All tr-AEs were effectively managed through a proactive protocol: routine weekly blood monitoring and timely use of platelet-boosting agents for thrombocytopenia; pre-cycle quantitative urine tests and dose adjustment/interruption of bevacizumab for proteinuria; and optimization of TACE embolization combined with hepatoprotective drugs for transaminitis. Crucially, all events were controllable via temporary drug withholding, dose modification, or symptomatic support, and no treatment-related deaths occurred.

Multivariate analysis identified MVI as an independent risk factor for both OS (HR = 2.15, P = 0.045) and PFS (HR = 2.74, P = 0.011) in our cohort—consistent with Qin et al.’s findings (HR = 3.13 for OS, HR = 2.55 for PFS) (28) and EMERALD-1’s subgroup analysis, which showed poorer progression-free survival in patients with MVI (HR = 1.12 vs. 0.73 for non-MVI patients) (17). MVI is a well-recognized marker of aggressive tumor biology, as it indicates tumor cell invasion into major vascular structures and increased risk of extrahepatic metastasis. Multivariate analysis in previous study reported that MVI was significantly associated with tumor necrosis by TACE (P <0 .02), and the strongest factor for recurrence-free survival rate within 2 years (P = 0.002) (29). These observations imply that prevention of macrovascular invasion may help improve clinical outcomes.

In the present study, patients with baseline AFP ≥ 400 ng/mL had significantly poorer overall survival compared with those with AFP < 400 ng/mL, which is consistent with previous reports (30), suggesting that elevated AFP is closely associated with unfavorable long-term prognosis in patients with hepatocellular carcinoma. However, no significant difference in progression-free survival was observed between patients with high and low AFP levels, indicating that AFP may have a limited impact on short-term disease progression. In contrast, liver cirrhosis was not significantly associated with either overall survival or progression-free survival, demonstrating that prognosis in this combination treatment setting may be driven more by tumor-related factors than by underlying cirrhotic status.

Several limitations of this study should be acknowledged. First, the retrospective, single-center design with a modest sample size may introduce selection bias. Second, the absence of a control group limits the ability to directly compare efficacy with other regimens, and thus the conclusions are drawn from indirect comparisons with historical data. Third, although the first-line treatment was standardized, subsequent therapies after progression varied among patients, which may have confounded the survival analysis. Future large-scale, multicenter, prospective randomized trials are warranted to validate these findings and further establish the generalizability of this combination strategy.

In conclusion, our study suggests that the combination of TACE with sintilimab and bevacizumab provides a safe and effective therapeutic option for patients with HCC, showing considerable promise in enhancing treatment efficacy and improving clinical outcomes.