Hepatocellular carcinoma (HCC) is the sixth most common malignancy and fourth leading cause of cancer-related death worldwide. According to the National Cancer Institute SEER database, the average 5-year survival rate of patients with HCC in the USA is 19.6%, but can be as low as 2.5% for advanced, metastatic disease (1,2). A total of >90% of HCC cases develop in individuals with preexisting chronic liver conditions, making this cancer a significant contributor to morbidity and mortality among patients with cirrhosis (3). The poor prognosis for patients with HCC has traditionally stemmed from a combination of late-stage diagnosis and limited treatment effectiveness at advanced stages.

Systemic therapy continues to be the preferred treatment modality for patients diagnosed with unresectable HCC (uHCC). Among the available options, tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, demonstrate similar overall survival (OS) outcomes for patients with uHCC (range, 10–13.5 months) (4–6). Lenvatinib, a multi-TKI, acts on receptors that include platelet-derived growth factor receptor-α, rearranged during transfection and tyrosine-kinase receptor (7). This inhibition effectively curtails angiogenesis and hinders tumour growth. Its robust suppression of the fibroblast growth factor receptor (FGFR) pathway is the key approach to managing liver cancer. In the REFLECT trial, lenvatinib exhibited superior response rates, extended progression-free survival and demonstrated non-inferiority in OS compared with sorafenib (4). Although lenvatinib has shown superiority to sorafenib in improving OS in patients with HCC in clinical trials (clinical trials nos. NCT01761266 and NCT04127396), its effectiveness has been limited by resistance and side effects (4). Further improvements in efficacy are required.

In recent years, immune checkpoint inhibitors have been widely studied in various cancers. Programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) checkpoint inhibitors have emerged as promising treatment strategies for HCC (8). Currently, an increasing body of evidence indicates that most TKIs exert anti-angiogenic activity in cancer treatment, and when used in combination with immunosuppressants, including PD-1 blockade, sirolimus and everolimus, they exhibit a synergistic effect (9). TKIs can promote the expression of major histocompatibility complex antigens on tumour cells, thereby enhancing sensitivity to T-cell-mediated tumour cell elimination. This effect is particularly pronounced when used in combination with PD-1 inhibitors as it facilitates T-cell-mediated tumour cell destruction (10). In vitro studies have shown that lenvatinib and PD-1 inhibitors can exert synergistic antitumour effects (11,12). In addition, an early clinical trial regarding the combination of lenvatinib and PD-1 inhibitors for advanced HCC has reported favourable safety and effectiveness (13). However, to date, evidence-based information on the efficacy and safety of lenvatinib combined with PD-1/PD-L1 inhibitors in treating HCC is lacking. A meta-analysis of the clinical survival indicators, adverse reactions and safety of lenvatinib combined with PD-1 inhibitors in liver cancer treatment was conducted, providing objective and effective evidence-based medical information for clinical use. The present study is anticipated to guide clinical application.

The growing body of evidence underscores the significance of FGF pathway signalling activation in HCC development and advancement (22). Matsuki et al (23) conducted a thorough investigation, using in vitro experiments with human HCC cell lines and in vivo studies with mouse xenograft models. That study confirmed that the FGF19-FGFR4 axis plays a pivotal role in markedly augmenting the proliferation and growth of HCC. These discoveries provide a compelling explanation for the treatment responses witnessed with lenvatinib, a potent inhibitor designed to target FGFR 1–4, particularly in advanced HCC cases (4).

Lenvatinib, similar to other multi-kinase inhibitors, has demonstrated its capacity for immunomodulation (24). Notably, VEGF-A and β-FGF have been identified as potent inducers of immune checkpoint markers while concurrently inhibiting the secretion of IFN-γ and granzyme B, consequently dampening T-cell cytotoxicity (25). Notably, lenvatinib can reverse this immunosuppressive effect (11). Additionally, Adachi et al (25) elucidated that the activation of FGFR signalling leads to the suppression of the JAK/STAT pathway, resulting in IFN-γ secretion reduction. Nevertheless, the use of lenvatinib, which inhibits FGFR signalling, efficiently reinstates the stimulation of IFN-γ (25). Furthermore, multiple studies have shown that lenvatinib elevates the proportion of activated CD8⁺ T cells that secrete IFN-γ and granzyme B (25,26). The antitumour efficacy of lenvatinib was diminished in immunodeficient mice when CD8⁺ T cells were depleted (26). Conversely, lenvatinib reduced the percentage of monocytes and the population of macrophages, including tumour-associated macrophages (TAMs) (25,26). In summary, lenvatinib has been observed to enhance antitumour immunity by increasing the population of IFN-γ-producing CD8⁺ T-cells and reducing the presence of TAMs. These findings suggest that lenvatinib may hold the potential for combination therapy with immunotherapy approaches.

The present meta-analysis included six studies to analyse the efficacy and safety of lenvatinib combined with PD-1/PD-L1 inhibitors and lenvatinib monotherapy in HCC treatment. In summary, the current study demonstrates the potential synergistic effects of combining lenvatinib with PD-1/PD-L1 inhibitors in HCC treatment. The improved ORR and DCR observed in the combination therapy group compared with those in the lenvatinib monotherapy group suggest that this approach is promising for enhancing treatment outcomes. However, the increased efficacy primarily manifested as PR, and the difference in CRs between the combination therapy and lenvatinib monotherapy groups was not statistically significant. The failure of combination therapy to significantly enhance CR rates suggests that specific biological or microenvironmental factors, such as immunosuppressive cells (27) and proinflammatory cytokines (28), in HCC may contribute to resistance against complete eradication. Understanding the mechanisms behind this limitation could direct future therapeutic strategies. Further research and clinical trials are warranted to explore the mechanistic basis of these observations, optimize patient selection criteria, and assess the long-term benefits and potential toxicities associated with this therapeutic approach.

The present subgroup analyses, which focused on the PD-1/PD-L1 inhibitors nivolumab and camrelizumab provided valuable insights into the variations in DCR associated with these specific combinations. The pooled results clearly demonstrated that combination therapy using lenvatinib and nivolumab led to a significantly higher DCR than that of lenvatinib monotherapy. This finding underscores the potential synergy between lenvatinib and nivolumab in effectively controlling the progression of HCC. The improved DCR suggests that this combination may be particularly beneficial for patients with HCC who seek enhanced disease control and tumour burden reduction. By contrast, the current analysis did not reveal a significant difference in DCR between combination therapy using lenvatinib and camrelizumab, and lenvatinib monotherapy. While this result might suggest a limited additive effect when using lenvatinib and camrelizumab in terms of DCR, it is noteworthy that clinical outcomes may be influenced by various factors, including patient heterogeneity and tumour characteristics. Overall, these subgroup analyses emphasize the need for the careful selection of PD-1/PD-L1 inhibitors when combining them with lenvatinib in the treatment of HCC. The choice of PD-1/PD-L1 inhibitor could significantly impact therapeutic response, and further research is warranted to explore the underlying mechanisms behind these observed differences. Personalized treatment approaches, tailored to individual patient profiles, may ultimately provide the most effective outcomes in the context of combination therapies for HCC.

In addition, the pooled results showed that there was no significant difference in the incidence rate of adverse events from combination therapy using lenvatinib and PD-1/PD-L1 inhibitors, and lenvatinib monotherapy in the treatment of HCC, suggesting that patients should be fully informed of possible adverse reactions before treatment and that further treatment should be carried out after patient consent. Timely treatment is needed to prevent possible adverse reactions.

The current study still had some limitations: i) The sample size of the included literature was small, which may lead to the risk of bias in the results; a large sample and multicentre RCT studies are needed; ii) the intervention was lenvatinib combined with PD-1 inhibitors, however, due to the difference in dosage between studies and the different response effects of patients with liver cancer to related drugs, the results of the present meta-analysis were affected to some extent; and iii) there is a possible publication bias in the analysis of the ORR, hence, it is necessary to continue to include new studies in future studies to exclude the risk of bias.

Compared with lenvatinib monotherapy, lenvatinib combined with PD-1/PD-L1 inhibitors significantly improved the ORR, mainly PR, and DCR in patients with HCC. It is noteworthy that lenvatinib was mainly combined with nivolumab to increase the DCR of lenvatinib monotherapy for HCC. In addition, there was no significant difference in the incidence rate of adverse reactions between combination therapy and lenvatinib monotherapy for HCC.