Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third leading cause of cancer-related deaths (1). Despite advances in screening, liver function protection, and surgical techniques, the prognosis remains suboptimal. The five-year recurrence rate is as high as 70% (2). High-risk subgroups, particularly those with large tumor burden and multifocal distribution, face a significantly increased risk of postoperative recurrence (3, 4). This is a key factor limiting long-term survival.

The “up-to-seven” criteria, which combine the largest tumor diameter and the number of nodules, offer a concise and practical method for assessing tumor burden (5). This tool has been widely adopted for risk stratification in liver transplantation and liver resection patients (6). However, patients exceeding these criteria often demonstrate greater biological invasiveness and tumor heterogeneity. They have a limited response to traditional treatments and significantly poorer postoperative survival compared to those within the criteria (7, 8). For this high-risk population, effective perioperative management strategies remain scarce, highlighting the need for more synergistic treatment approaches.

Recently, neoadjuvant therapy has gained attention in the treatment of HCC (9, 10). Neoadjuvant therapy has proven effective in reducing tumor size and improving postoperative survival outcomes in various solid tumors (11). In HCC, its theoretical foundation is well-established. Primary tumors can continue to release antigens while intact, promoting tumor-specific T cell expansion and remodeling the immune microenvironment. This enhances the response to immune checkpoint inhibitors (ICIs) (12). Preliminary clinical studies have explored the potential of neoadjuvant immunotherapy and combination treatments in downstaging HCC and improving long-term prognosis (13–15). However, most of the available evidence remains exploratory, and there is a lack of systematic studies focusing on the high-risk beyond “up-to-seven” population.

The combination of transarterial chemoembolization (TACE), PD-1/PD-L1 inhibitors, and multi-target tyrosine kinase inhibitors (TKIs) has been extensively studied in advanced HCC (16, 17). This regimen not only exhibits direct antitumor effects, but also induces tumor antigen release, remodels the tumor immune microenvironment (TIME), promotes immune cell infiltration, and inhibits immune escape. These effects synergistically enhance antitumor activity (18–20). Early real-world studies have demonstrated higher objective response rates, prolonged progression-free survival (PFS), and a favorable safety profile in advanced HCC (21, 22). Given its potential for tumor shrinkage and systemic control, this triple regimen is anticipated to be an effective preoperative strategy for patients beyond the “up-to-seven” criteria. It can help achieve tumor downstaging, reduce postoperative recurrence risk, and prolong long-term survival.

There are currently no systematic studies examining the use of this triple neoadjuvant therapy in patients with beyond “up-to-seven” HCC. To address this gap, this study retrospectively analyzes the prognosis and safety outcomes between patients with beyond “up-to-seven” HCC who underwent successful liver resection after preoperative TACE combined with immunotherapy and targeted therapy, and those who underwent surgery alone. The aim is to provide evidence-based recommendations and practical references for perioperative management strategies in this high-risk population.

This study, based on real-world data, evaluated the postoperative efficacy and safety of preoperative systemic therapy in HCC patients exceeding the “up-to-seven” criteria. After controlling for confounding factors using PSM, the PST group showed significantly better RFS and OS compared to the surgery-only group, with no increase in perioperative complication risk. These findings suggest that preoperative systemic therapy holds potential clinical value in high-risk, beyond “up-to-seven” HCC populations. After matching, both groups were well balanced in terms of baseline characteristics, such as age, sex, BCLC stage, tumor burden, and liver function, effectively reducing confounding bias. The PST group demonstrated superior survival outcomes, further supporting the use of neoadjuvant therapy in HCC patients with high tumor burden and high postoperative recurrence risk. Multivariate analysis identified preoperative systemic therapy as an independent protective factor for both RFS and OS, while tumor diameter and elevated ALT levels were independent adverse prognostic factors. This suggests that both tumor size and potential liver inflammation may jointly impact treatment efficacy. Exploratory subgroup analyses further support the robustness of our findings. In the post-PSM cohort, the survival advantage of PST was preserved across subgroups defined by MVI and histologic differentiation. The benefit reached statistical significance in MVI-positive patients, whereas in MVI-negative patients the differences did not achieve significance but remained directionally consistent, likely reflecting limited sample size and event numbers. Similarly, consistent benefits of PST were observed across differentiation subgroups, supporting the applicability of this strategy irrespective of tumor grade. Together, these results strengthen confidence in the stability of our primary outcomes and provide a solid foundation for comparison with prior neoadjuvant experiences in HCC and other solid tumors.

These findings are consistent with the growing trend of applying neoadjuvant therapy across solid tumors. Prior studies have shown that neoadjuvant therapies significantly improve pathological response and RFS in lung cancer, as well as PFS in melanoma (25, 26). In HCC, preoperative ICIs also show promise. Research indicates that 32% of HCC patients receiving neoadjuvant ICIs achieve major pathological response (MPR), and 18% achieve pathological complete response (pCR), significantly extending postoperative RFS (27). Building on these findings, our study advances the application of systemic therapy to the preoperative phase, focusing on the high-recurrence-risk beyond “up-to-seven” subgroup, providing further evidence for this approach. Notably, the IMbrave050 study’s subgroup analysis showed that, even in patients whose tumor burden exceeded the “up-to-seven” criteria, adjuvant therapy with atezolizumab and bevacizumab resulted in a trend of improved RFS. This further supports the potential value of immune combination strategies in high-risk HCC patients (28), and raises the question of the biological mechanisms underlying these benefits.

From a mechanistic perspective, the preoperative triple treatment regimen offers multiple synergistic anti-tumor effects (29). In this study, TACE was combined with systemic agents (TKIs and PD-1 inhibitors) as an integrated neoadjuvant regimen. Accordingly, the mechanistic rationale and clinical implications should be understood in the context of this combined loco-regional plus systemic approach, rather than TACE in isolation. TACE induces local hypoxia by blocking tumor blood supply, which activates HIF-1α and upregulates pro-angiogenic factors such as VEGF and PDGF. This can promote tumor angiogenesis (29, 30). Simultaneously, chemotherapy agents released during TACE induce tumor cell necrosis, antigen release, and inflammatory factor expression, enhancing tumor immunogenicity and converting “cold tumors” into “hot tumors,” thus improving immune therapy efficacy (18, 31, 32). TKIs block VEGF/PDGF signaling pathways, providing both anti-angiogenic and direct anti-cancer effects. These counteract the pro-angiogenic effects induced by TACE and enhance immune sensitivity by improving the tumor microenvironment (33, 34). However, TKIs may also exacerbate tumor hypoxia, leading to upregulation of PD-L1 expression, which may activate immune suppression and promote immune escape (35, 36). In this context, PD-1/PD-L1 inhibitors can relieve immune suppression, restore T-cell function, and reestablish tumor immune surveillance (37, 38). Preclinical and translational studies further suggest that TKIs augment PD-1 activity by improving antigen presentation and limiting suppressive cell infiltration (34). Importantly, systemic immune activation during the preoperative phase may induce immune memory before postoperative tolerance develops, enabling long-term surveillance of residual disease (12). In summary, this neoadjuvant triple regimen offers complementary and synergistic mechanisms that reduce tumor burden, optimize resection conditions, and potentially prolong long-term survival. Beyond HCC, the rationale of combining locoregional and systemic strategies is supported by evidence from other malignancies. Biomarker-driven interventions have been shown to reshape treatment outcomes in esophageal cancer, underscoring the importance of tailoring systemic therapy to biological context (39). Likewise, targeting both cancer cells and the tumor microenvironment represents a therapeutic principle highly relevant to our approach (40). Broader oncologic reviews have emphasized the historical evolution and future promise of combination therapy, situating our findings within this larger treatment paradigm (41). In addition, biomarker discovery is increasingly informing drug development and patient stratification (42), while the challenge of T cell exhaustion remains central to immunotherapy resistance. Recent studies identifying novel exhaustion markers in CD8⁺ T cells provide important mechanistic insight and further rationale for PD-1 based strategies in HCC (43).

In terms of safety, the PST group experienced significantly longer surgical times and a trend toward higher intraoperative blood loss compared with the Surgery group. These findings suggest that preoperative therapy may increase surgical complexity, potentially due to treatment-induced liver fibrosis, inflammation, or altered vascular supply. Importantly, however, this increased technical difficulty did not translate into higher perioperative risk. The overall complication rate within 30 days was comparable between groups, and severe complications (Clavien–Dindo grade ≥ III) occurred in only one patient in the Surgery group. These results indicate that, while resections after PST may be more demanding for the surgical team, the procedure remains safe in experienced centers. Most adverse events related to the neoadjuvant therapy were grade 1–2, with few grade 3–4 events, and the majority of patients successfully completed the planned treatment. Taken together, these findings support the feasibility and tolerability of the PST regimen. Future studies incorporating pathological and imaging correlates will be valuable to further elucidate the mechanisms underlying these operative changes and to optimize perioperative management.

This study has several limitations. First, the analytic cohort was restricted to patients who ultimately underwent curative-intent resection. Patients who failed to proceed to surgery were not included, as they lay outside the scope of this comparative analysis. This design ensured comparability with the direct surgery group and is consistent with previous large retrospective studies (44). Nevertheless, such exclusion inevitably introduces selection bias, as it preferentially retains patients with more favorable tumor biology and treatment tolerance. Consequently, the survival benefit of PST observed in this study may be overestimated, and the survival curves may appear more optimistic than would be expected in an intention-to-treat population. Second, the retrospective design and relatively small sample size limit the strength of the conclusions, as residual confounding from unmeasured variables (e.g., performance status, comorbidities, socioeconomic factors) cannot be fully excluded despite propensity score matching. In addition, the limited number of survival events—particularly for OS—raises the risk of overfitting in the multivariate Cox regression models, and these results should therefore be interpreted with caution. Third, treatment heterogeneity existed within the PST group in terms of both the specific PD-1 inhibitors and the number of TACE sessions. We reported the regimen distribution descriptively, but did not attempt to compare outcomes across regimens due to limited subgroup sizes. This heterogeneity reflects real-world MDT practice, yet it may affect the interpretation of results. Finally, mechanistic insight was constrained by the absence of biomarker correlates such as immune infiltration, PD-L1 status, or cfDNA kinetics, since biospecimens were not adequately preserved for this retrospective cohort. These limitations highlight the need for prospective, multicenter trials with standardized treatment protocols and integrated biomarker analyses to confirm the true clinical value and biological underpinnings of this strategy.

In conclusion, this study suggests that preoperative TACE combined with PD-1 inhibitors and TKIs is associated with improved survival and acceptable safety in patients with beyond “up-to-seven” HCC. This combined strategy may represent a promising perioperative option for high-risk patients and warrants validation in prospective studies to confirm its clinical value.