Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent malignancy worldwide and the fourth in tumor-related mortality, with a significant global health burden (1). Despite advances in medical technology, the prognosis for HCC patients continues to be poor due to high recurrence rates following surgical intervention. Several studies have indicated that approximately 50-70% of patients suffered from recurrence within five years after hepatectomy (2–4). Curative hepatectomy, the standard treatment for resectable HCC (5), often fails to prevent recurrence, necessitating the exploration of effective adjuvant therapies.

Adjuvant treatments aim to reduce the risk of recurrence and improve overall survival rates (6). In recent years, immunotherapy and targeted therapy have gained significant attention for their potential benefits in HCC management (7–10). In a global, open-label phase 3 study (IMbrave050), improved recurrence-free survival was observed in high-risk hepatocellular carcinoma patients who received atezolizumab plus bevacizumab following curative resection or ablation, compared with those who underwent active surveillance (11). However, previous trials assessing single-agent adjuvant therapy have yielded negative or inconclusive results. The STORM study, which evaluated sorafenib as adjuvant therapy after resection or ablation, failed to show improvement in recurrence-free survival (RFS) or overall survival (OS) compared to placebo (12). Similarly, the CheckMate 9DX and KEYNOTE-937 phase III trials are ongoing to assess the role of adjuvant PD-1 monotherapy (nivolumab and pembrolizumab, respectively), but results are not yet available. These trials illustrate the limitations of monotherapy approaches and underscore the need to explore more effective combination strategies.

Another multicenter phase III randomized controlled trial (RCT) indicated that FOLFOX-based hepatic arterial infusion chemotherapy (FOLFOX-HAIC) significantly lowered the recurrence risk and improved survival in hepatocellular carcinoma patients with microvascular invasion (MVI). The median disease-free survival (DFS) was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = 0.001) (13). Collectively, these findings highlight the promising role of adjuvant therapies in enhancing outcomes after curative hepatectomy for HCC. Yet, a globally accepted standard adjuvant treatment protocol remains elusive.

Beyond clinical efficacy, the evolving role of cancer immuno-oncology (IO) in HCC has highlighted the importance of identifying predictive biomarkers and characterizing the tumor immune microenvironment (TIME) to optimize therapeutic benefit. Importantly, TIME fundamentally shapes the expression and prognostic relevance of these biomarkers, thereby linking immune contexture with therapeutic responsiveness. Features such as PD-L1 expression, α-fetoprotein (AFP), immune gene signatures, and tumor-infiltrating lymphocytes have been studied for their potential to predict responsiveness to immunotherapy (14–16). Among these, PD-L1 expression has been investigated as a key biomarker, with higher expression levels generally correlating with improved response to checkpoint inhibitors, though its predictive value remains inconsistent due to heterogeneity in detection methods and tumor biology (17, 18). Similarly, early dynamic changes in AFP levels during treatment have shown promise as a non-invasive predictor of treatment response and survival outcomes, providing practical utility in clinical monitoring despite its limitations in AFP-negative patients (19, 20). Additionally, the presence of an “immune-excluded” or “immune-desert” microenvironment in HCC has been associated with resistance to immune checkpoint blockade, suggesting that personalized approaches may be necessary (21–23). These advances support the growing need to integrate immune landscape characterization into treatment planning. Furthermore, novel immunotherapeutic strategies including adoptive T-cell therapies and oncolytic virotherapy are under investigation, expanding the horizon of immune-oncology (IO) in HCC (24–26). These emerging modalities may eventually be combined with existing checkpoint inhibitors or targeted therapies to improve efficacy.

Given the limitations of existing adjuvant therapies, novel combinations such as Tislelizumab and Lenvatinib are being explored for their potential to address the high recurrence rates post-surgery. Tislelizumab, an immune checkpoint inhibitor targeting PD-1, has shown promise in enhancing the immune response against tumor cells (27, 28). Its efficacy and non-inferiority to sorafenib in advanced HCC have been demonstrated in the RATIONAL 301 phase III trial, which showed comparable overall survival and a more favorable safety profile, supporting its potential for broader application in HCC management (29). Concurrently, Lenvatinib, an inhibitor of multiple receptor tyrosine kinases, has demonstrated efficacy in inhibiting tumor angiogenesis and proliferation (30–32). The pivotal REFLECT study established Lenvatinib as a non-inferior alternative to sorafenib in first-line treatment of unresectable HCC, with superior progression-free survival and objective response rate (33). The synergistic effect of these agents could potentially offer a robust strategy to prevent HCC recurrence after surgery.

Inspired by the success of the IMbrave050 regimen and the biological rationale for combining immune checkpoint blockade with anti-angiogenic therapy, the combination of Tislelizumab plus Lenvatinib may offer a similarly synergistic strategy in the adjuvant setting. This study aims to assess the prognostic impact of Tislelizumab plus Lenvatinib as adjuvant therapy, providing critical insights into their potential to improve disease-free survival and overall survival in HCC patients following curative hepatectomy. The results of such studies could redefine the therapeutic landscape for HCC and offer new hope for patients undergoing curative hepatectomy.

Hepatectomy remains a cornerstone curative treatment for hepatocellular carcinoma, offering the potential for long-term survival (4). Nevertheless, postoperative recurrence continues to pose a major clinical challenge, significantly compromising long-term outcomes (37, 38). Given the limited therapeutic options available once recurrence occurs, preventing postoperative relapse is of paramount importance. While adjuvant therapies have shown promise in reducing recurrence and improving survival, no consensus exists regarding the optimal postoperative regimen for HCC (39). This underscores an urgent unmet need in clinical practice. Against this backdrop, our study investigated the prognostic effect of adjuvant tislelizumab combined with lenvatinib following curative hepatectomy, aiming to provide real-world insights into this critical area of clinical uncertainty.

Our study demonstrated that adjuvant tislelizumab plus lenvatinib significantly prolonged median DFS (40.78 months) and OS (42.10 months) in patients undergoing curative hepatectomy. These findings align with previous studies exploring adjuvant therapies in HCC. A randomized trial reported that adjuvant transarterial chemoembolization (TACE) significantly improved median DFS (17.45 months vs. 9.27 months, HR = 0.70, P = 0.020) and OS (44.29 months vs. 22.37 months, HR = 0.68, P = 0.029) in patients with single tumors >5 cm and MVI (40). Similarly, a phase III clinical trial demonstrated that FOLFOX-HAIC significantly prolonged DFS in MVI-positive patients (20.3 months vs. 10.0 months, HR = 0.59, P = 0.001), although no significant OS benefit was observed (13). Notably, while TACE and HAIC have shown survival benefits, they are invasive procedures associated with additional procedural risks and complications. In contrast, the combination of targeted therapy and immunotherapy in this study not only achieved survival outcomes comparable to or even exceeding those reported with postoperative TACE/HAIC but also minimized procedural invasiveness, potentially improving patient compliance and tolerability. These findings highlight the promise of immunotherapy-based strategies as a non-invasive yet effective approach for improving long-term outcomes in postoperative HCC patients.

In the present study, HBV infection, macrovascular invasion, and postoperative adjuvant therapy emerged as independent prognostic factors influencing both disease recurrence and overall survival. The prognostic impact of HBV infection and macrovascular invasion has been well documented, as both factors are closely linked to tumor aggressiveness, increased recurrence rates, and poor long-term outcomes in patients undergoing hepatic resection for HCC (41–43). In contrast, the role of postoperative adjuvant therapy, particularly systemic therapy involving targeted agents and immune checkpoint inhibitors, remains less clearly defined. Notably, the IMbrave050 trial marked a breakthrough by establishing the potential of atezolizumab plus bevacizumab as an adjuvant regimen following resection or ablation. While this study confirmed a significant benefit in recurrence-free survival, it did not yet provide mature data on overall survival (11). Similarly, a recent multicenter phase 2 randomized trial in China evaluated adjuvant sintilimab in HCC patients with microvascular invasion and demonstrated a significant improvement in recurrence-free survival compared to active surveillance (27.7 vs. 15.5 months; HR = 0.534; P = 0.002), though OS data remain immature (10). Compared to our findings, which showed longer DFS and OS with combination therapy, the differences may stem from the limited efficacy of PD-1 monotherapy, shorter treatment duration (eight cycles of sintilimab), and relatively brief follow-up. Furthermore, several large-scale randomized trials are currently ongoing to evaluate various immune checkpoint inhibitors in the adjuvant setting, including CheckMate 9DX (nivolumab), EMERALD-2 (durvalumab plus bevacizumab), and KEYNOTE-937 (pembrolizumab). These studies are expected to provide more definitive guidance regarding optimal regimens, patient selection, and long-term survival benefit.

It is worth noting that most existing studies on adjuvant therapy have focused on patients with high-risk features, particularly those with MVI. However, in real-world clinical practice, the application of adjuvant systemic therapy has expanded to include selected patients without MVI based on individualized risk assessments. In our study, the proportion of MVI-positive patients was similar between groups, yet those receiving adjuvant tislelizumab plus lenvatinib exhibited significantly improved survival. This observation suggests that even patients lacking classical high-risk features may derive benefit from postoperative systemic therapy. One possible explanation is that other unfavorable pathological or intraoperative factors—such as poor differentiation, satellite nodules, or close surgical margins—may have influenced treatment decisions.

The current findings hold substantial clinical potential, especially for patients not eligible for locoregional adjuvant therapies or those intolerant to intensive chemotherapy. The ability to administer systemic therapy with manageable toxicity widens the scope of adjuvant treatment in clinical practice. Looking forward, key knowledge gaps include identifying which subpopulations derive the most benefit from immuno-targeted adjuvant therapy, determining optimal treatment durations, and integrating biomarker-driven patient selection. We anticipate that within the next five years, ongoing RCTs and real-world studies will refine clinical guidelines, possibly leading to the adoption of immuno-targeted combinations as standard postoperative strategies for selected HCC patients.

Regarding treatment-related adverse events (AEs), the overall incidence of AEs was comparable between the two groups. However, patients in the adjuvant therapy group experienced a higher frequency of hyperbilirubinemia and hypertension. Notably, grade 3/4 hypertension occurred more frequently in this group, though no AE-related deaths were reported. These findings suggest that while certain toxicities, particularly hypertension, may be more common with postoperative immuno-targeted therapy, the safety profile remains generally manageable. With appropriate monitoring and supportive care, most AEs were controllable and did not compromise the continuation of treatment.

As a retrospective study, our research inevitably carries certain limitations, including potential selection bias and limited control over confounding variables. Moreover, the relatively small sample size may restrict the generalizability of the findings. While propensity score matching was attempted, the resulting sample size was insufficient for robust statistical analysis. Nevertheless, our study offers a novel perspective: in the current era where immunotherapy and targeted therapy are increasingly prevalent, postoperative adjuvant therapy may confer additional survival benefits without substantially increasing postoperative complications. More importantly, the potential benefit observed even in patients beyond classical high-risk categories highlights a possible paradigm shift toward broader use of systemic immuno-targeted strategies in the adjuvant setting. Future large-scale prospective trials are essential to confirm these findings and refine patient selection criteria.

Adjuvant Tislelizumab and Lenvatinib after curative hepatectomy holds significant potential benefits with manageable adverse events.