Correlation of radiotherapy, targeted therapy, and immunotherapy with hepatocellular carcinoma recurrence

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors globally and is the most prevalent type of primary liver cancer, posing a heavy burden on global health. Surgical resection and liver transplantation are the gold standard for the radical treatment of HCC. However, due to the heterogeneity and high invasiveness of HCC, the rates of local and distant recurrence are extremely high, with over 70% of patients experiencing recurrence within 5 years after treatment, significantly impacting the long-term quality of life. Therefore, researchers are exploring other treatment methods to reduce tumor recurrence and improve patient survival. To date, extensive research has concentrated on new alternative therapies, including radiotherapy (e.g., selective internal radiotherapy), targeted drug therapy (e.g., sorafenib and lenvatinib), and immunotherapy (e.g., immune checkpoint inhibitors), which have played an integral role in the comprehensive treatment of HCC. This review mainly focuses on the cutting-edge advancements in these treatment methods for HCC and their potential role in reducing HCC recurrence.

Key Words: Hepatocellular carcinoma; Tumor recurrence; Radiotherapy; Targeted Therapy; Immunotherapy; Treatment strategies

Core Tip: Hepatocellular carcinoma (HCC) is a prevalent cancer worldwide, ranking as the third leading cause of cancer-related deaths. Despite advancements in treatment modalities, a significant proportion of patients with HCC (50%-70%) experience tumor recurrence within 5 years of initial treatment. This review focuses on the roles of radiotherapy, targeted therapy, and immunotherapy in managing post-surgical HCC recurrence and their combined effects.

INTRODUCTION

Hepatocellular carcinoma (HCC) is among the most prevalent cancers worldwide, ranking as the third leading cause of cancer-related deaths, surpassed only by lung and colorectal cancers[1]. Chronic liver diseases, including those caused by hepatitis B virus, hepatitis C virus, alcoholic liver disease, and nonalcoholic fatty liver disease, are major etiological factors in HCC development[2]. Despite advancements in treatment modalities, including hepatic resection and ablation techniques, a significant proportion of patients with HCC (50%-70%) experience tumor recurrence within 5 years of initial treatment[3]. This recurrence may be attributed to intratumoral spread due to microvascular invasion (MVI) and satellite nodules or the emergence of new, independent cancerous lesions[4]. Current effective treatment strategies for HCC include surgical resection, liver transplantation (LT), and locoregional ablative therapies, which offer high success rates in early-stage patients. However, the complex pathophysiology and insidious nature of HCC often lead to diagnosis at an unresectable stage[5]. Even in patients who undergo surgical resection, recurrence rates remain high. This underscores the urgent need for more effective adjuvant therapies and a shift towards combination treatment strategies to reduce recurrence rates and prolong survival. This review focuses on the roles of radiotherapy, targeted therapy, and immunotherapy in managing post-surgical HCC recurrence and their combined effects.

CLASSIFICATION OF HCC RECURRENCE

HCC recurrence can be categorized based on the site of recurrence as local recurrence, defined as tumor reappearance in the vicinity of the primary lesion, and distant recurrence, characterized by cancer cell metastasis to sites outside the liver, such as the lungs or bones. Intrahepatic recurrence is the main recurrence pattern of HCC[6]. The unique anatomical structure of the hepatic sinusoids significantly prolongs the retention time of HCC cells, while the barrier function of the extracellular matrix in the liver increases the difficulty of HCC cells metastasizing outside the liver[7,8]. Even if HCC cells manage to escape the liver, they still face numerous challenges during metastasis, including a long metastatic pathway, mechanical damage from blood flow shear forces, and changes in the immune microenvironment[9,10]. A large, Chinese multicenter study demonstrated that recurrence occurred in 41.3% of patients more than two years post-treatment. Of these recurrences, 90.1% were exclusively intrahepatic, while the remainder involved both intrahepatic and extrahepatic sites. Purely extrahepatic recurrence was not observed[11]. This suggests a strong association between intrahepatic and extrahepatic recurrence, indicating that distant metastases may originate from or be closely linked to local recurrence.

Another common classification system differentiates between early and late recurrence based on the time elapsed since initial treatment. Early recurrence is generally associated with factors related to the primary tumor, while late recurrence is often linked to the development of a new and independent HCC. The prevailing view is that early recurrence should be defined as recurrence within 2 years post-surgery or treatment, whereas late recurrence occurs after 2 years[12]. Currently, there is no universally accepted standard for defining the timeframes separating early and late recurrence. Typically, researchers utilize the minimum P value approach to determine the time cutoff separating early and late recurrence. Huang et al[13] retrospectively analyzed 82 HCC patients who underwent multiple hepatectomies for recurrence, identifying 18 months post-initial resection as a significant timepoint distinguishing intrahepatic metastasis from multicentric occurrence. Employing a similar methodology, Xing et al[14], in a multicenter study of 1501 HCC patients, used multivariate logistic regression analysis to establish eight months as the optimal threshold for defining early HCC recurrence.

However, with the increasing demands for the treatment and prediction of liver cancer recurrence, binary classification methods have become insufficient to meet these requirements. Désert et al[15] constructed a comprehensive HCC transcriptomic meta-dataset and utilized RNA sequencing (RNA-seq) technology to identify two novel subtypes of HCC characterized by well-differentiated histology and low metastatic potential, namely periportal-type (wild-type CTNNB1) and perivenous-type (mutant CTNNB1). These novel HCC subtypes exhibit distinct early recurrence characteristics with low recurrence rates in the early postoperative period (< 2 years after resection). From the perspective of molecular typing, this classification provides a new approach for HCC recurrence classification[15]. A multicenter study from China involving 1319 patients with recurrent HCC identified four new recurrence subtypes. This classification was based on a comprehensive analysis of clinicopathological and biological characteristics. The subtypes were: Type I (single intrahepatic recurrence); Type II (multiple intrahepatic recurrences); Type III (progressive recurrence); and Type IV (rapidly progressive recurrence). Types III and IV showed significantly higher rates of p53 mutations, CCND1 amplification, faster growth and spread, metabolic problems, and immune suppression, leading to much poorer outcomes[16]. This study provides a more nuanced classification of recurrent HCC by incorporating a broader range of factors, offering deeper insights into recurrence mechanisms and providing valuable guidance for predicting post-treatment survival and informing treatment strategies.

ROLE OF RADIOTHERAPY IN HCC TREATMENT AND RECURRENCE CONTROL

Radiotherapy has become an increasingly important component of HCC treatment, particularly in advanced stages where surgical resection is challenging or impossible, serving as a crucial locoregional treatment modality. By precisely targeting the tumor, radiotherapy effectively controls tumor growth and significantly improves patient quality of life. The core principle of radiotherapy is the use of ionizing radiation (e.g., X-rays, gamma rays, electron beams) to deliver energy that directly or indirectly induces irreversible damage to tumor cells[17].

Radiotherapy is broadly categorized into two: External beam radiotherapy (EBRT) and internal radiotherapy (brachytherapy). EBRT delivers radiation from an external source, with technological advancements progressing from two dimensional-radiotherapy to three dimensional-conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and stereotactic body radiotherapy (SBRT), resulting in significantly improved treatment efficacy. Internal radiotherapy involves placing radioactive sources directly into or adjacent to the tumor. This usually includes intravascular brachytherapy (IVBT) using iodine-125 (I-125) and selective internal radiotherapy (SIRT) with yttrium-90 (Y-90) microspheres for HCC. The primary advantage of internal radiotherapy is its ability to deliver high-dose radiation precisely to the tumor, minimizing damage to surrounding tissues (Table 1).

Table 1 The mechanism of action of radiotherapy, efficacy in hepatocellular carcinoma recurrence, main limitations and relevant improvement strategies.

Type	Treatment	Mechanism	Efficacy	Limitations	Strategies	Ref.
External beam radiotherapy	3-DCRT	Adjust the direction of radiation beams based on the shape and location of the HCC lesion	3-DCRT significantly reduces the mortality and recurrence rates in resectable HCC patients with postoperative PVTT	Unsuitable for tumors with complex shapes or those located near critical organs	Replace with IMRT	Kim et al[18]; Wei et al[19]
	IMRT	Adjust the spatial distribution of a single radiation beam	The OS and RFS of patients with close surgical margins combined with IMRT are comparable to those of patients with wider surgical margins	Patients need a high number of treatment sessions and poor liver function exhibit poor tolerance	IMRT + SBRT	Wang et al[21]; Kim et al[24]
	SBRT	High-dose and high-selectivity radiation	Repeated SBRT for intrahepatic recurrent HCC is both safe and effective, with an overall 5-year local recurrence rate of only 6.3% (95%CI: 2.2%-13.4%)	High risk of liver damage outside the target area for multiple recurrent lesions	IMRT + SBRT; Repeated attempts at local control with close monitoring of liver function	Kimura et al[22];Kim et al[23];Kim et al[24];Ding et al[25]
Internal radiotherapy	IVBT (I-125)	γ-rays	Patients with high recurrence risk HCC, especially those with PVTT, demonstrate favorable treatment outcomes, with an ORR of 90% after one course of treatment	Poor systemic effects and inability to control micro-metastases; Incomplete radiation coverage; Patients with immunosuppression	TACE + sorafenib + I-125; Combined irradiation stent; 125I + CIK cells	Zhang et al[26];Huanget al[27];Lu et al[28];Zhang et al[29]
	SIRT (Y-90)	β-rays	In patients with PVTT, SIRT has been shown to significantly improve tumor response rates compared to sorafenib (19% vs 12%). Additionally, patients treated with Y-90 demonstrate a significantly reduced recurrence rate of HCC following LT and are more likely to achieve CPN	High cost; A certain risk of adverse events	Comprehensive pre-operative assessment	Gulec[30]; Hermann et al[32];Palmer et al[33];Chow et al[34];Dai et al[35];Agopian et al[36]

3-DCRT: Three dimensional-conformal radiotherapy; IMRT: Intensity-modulated radiotherapy; SBRT: Stereotactic body radiotherapy; SIRT: Selective internal radiotherapy; IVBT: Intravascular brachytherapy; HCC: Hepatocellular carcinoma; Y-90: Yttrium-90; I-125: Iodine-125; PVTT: Portal vein tumor thrombus; OS: Overall survival; RFS: Recurrence-free survival; ORR: Overall response rate; CI: Confidence interval; CPN: Complete pathological necrosis; CIK: Cytokine-induced killer; LT: Liver transplantation; TACE: Transarterial chemoembolization.

EBRT and HCC recurrence

3D-CRT is an early yet precise radiotherapy technique capable of adjusting the radiation beam’s trajectory based on the shape and location of liver cancer lesions. This allows higher radiation doses to be delivered specifically to the tumor while minimizing damage to surrounding healthy tissues and organs. Studies have demonstrated the survival benefits of 3D-CRT in patients with HCC and portal vein tumor thrombus (PVTT), a condition associated with high recurrence risk[18]. Recent research has further indicated that, in resectable HCC with PVTT, neoadjuvant 3D-CRT significantly reduces HCC-related mortality and recurrence rates compared to surgery alone [hazard ratios (HR) = 0.35, 95% confidence interval (CI): 0.23-0.54; P < 0.001] and 0.45 (95%CI: 0.31-0.64; P < 0.001)[19].

IMRT and SBRT are two advanced EBRT techniques developed from 3D-CRT[20], both of which show significant clinical value in managing liver cancer recurrence. IMRT enables precise modulation of radiation dose distribution delivered by each radiation beam, further reducing damage to surrounding healthy liver tissue. SBRT, on the other hand, delivers highly biologically effective doses over a shorter treatment course, providing superior local control. IMRT has been shown to improve 3-year overall survival (OS) and disease-free survival (DFS) in patients with HCC undergoing liver resection with narrow margins. A study of 181 patients with centrally located liver cancer demonstrated that those receiving IMRT following resection with narrow margins had OS and DFS rates comparable to those with wide resection margins[21].

Additionally, a multicenter retrospective study confirmed the safety and efficacy of repeat SBRT for intrahepatic recurrent HCC, reporting a 5-year local recurrence rate of just 6.3% (95%CI: 2.2%-13.4%), with most adverse effects being mild to moderate liver function impairment[22]. Specifically, in cases of solitary segmental recurrent tumors, high-dose SBRT exhibited significant efficacy in local and intrahepatic tumor control outside the treatment area, as well as overall patient survival[23]. However, SBRT carries a risk of liver function failure outside the target area, especially in patients with multifocal recurrence, necessitating close liver function monitoring. To achieve optimal outcomes, SBRT is typically implemented after multiple attempts at local control in patients with HCC[24].

Emerging evidence suggests that combining IMRT and SBRT offers significant clinical benefits in improving local control and long-term survival in patients with recurrent HCC[23,24]. This combined approach addresses the limitations of IMRT, including the requirement for multiple treatment sessions that may not be well-tolerated in patients with impaired liver function[25] and the limited efficacy of SBRT in multifocal disease[24], ultimately providing a safer and more effective treatment option for these patients.

Internal radiotherapy and HCC recurrence

IVBT is a form of internal radiotherapy that often uses I-125 seeds as radioactive implants, emitting gamma rays to damage tumor cell DNA while minimizing adverse reactions. Research on the use of I-125 for HCC has been extensive, particularly in patients with PVTT, known for their high recurrence rates. In one study involving computed tomography-guided implantation of I-125 seeds into 10 patients with PVTT and HCC, all patients survived the 4-month follow-up period. Among them, four achieved complete response (CR), five achieved partial response (PR), and one exhibited stable disease[26]. However, IVBT alone has certain limitations, including inadequate control of micro-metastases and incomplete tumor eradication. Combining IVBT with other treatments, such as transarterial chemoembolization (TACE) or sorafenib, has been shown to be significantly more effective in controlling intrahepatic tumors and PVTT, improving recurrence and progression patterns in patients with liver cancer[27]. Additionally, irradiation stents have been employed to address incomplete radiation coverage, ensuring that critical regions are exposed, thereby enhancing local control of recurrence-prone areas[28]. For patients with advanced HCC at high risk of recurrence, compromised immune function can reduce anti-tumor radiologic efficiency. Research suggests that combining IVBT with cytokine-induced killer cells can effectively improve patient survival by enhancing the immune response[29].

Y-90 is an advanced selective internal radiation therapy that has shown significant progress in treating liver cancer recurrence. Compared to low-dose intra-arterial brachytherapy, Y-90 SIRT delivers high-energy β-radiation directly to the tumor site by embedding the radioactive isotope Y-90 into glass or resin microspheres, which is administered through the hepatic artery. These β-rays selectively damage the DNA of tumor cells, suppressing their growth and spread while minimizing damage to the surrounding healthy liver tissue[30].

The SARAH trial, a multicenter phase III prospective study, was the first to compare the efficacy of SIRT with sorafenib[31]. Even in patients with portal vein invasion, SIRT demonstrated superior safety and quality of life, with significantly higher tumor response rates (19% vs 12%)[32]. Regarding progression-free survival (PFS), a subgroup analysis of the SARAH trial showed a median PFS of 6.7 months (95%CI: 3.9-9.5) for patients receiving Y-90 SIRT, compared to 3.7 months (95%CI: 3.2-9.5) for those treated with sorafenib. Although this difference was not statistically significant (HR = 0.65, 95%CI: 0.41-1.02; P = 0.06), it highlighted delayed disease progression with SIRT[33]. Moreover, SIRT caused fewer adverse effects and had better patient tolerability compared to sorafenib[34], further supporting its clinical potential.

Key factors preventing recurrence and improving survival outcomes during radiotherapy include tumor multiplicity, sufficient radiation dose, complete tumor necrosis, and tumor size (≥ 5 cm)[11,35], Y-90 is particularly effective in achieving superior local control and reduced recurrence, especially at higher radiation doses. In a localized study involving 73 patients with HCC undergoing LT, patients treated exclusively with Y-90 demonstrated significantly higher complete pathological necrosis (CPN) rates compared to those treated with TACE. When high radiation doses were achieved, necrosis rates reached 63%. Post-transplant recurrence rates were also significantly lower in the Y-90 group, with only 2% of patients experiencing recurrence and just 15% recurrence in cases without complete necrosis[36]. Another study emphasized the importance and safety of locoregional therapy before LT for HCC, noting that multimodal approaches combining radiotherapy with surgical resection are more likely to achieve CPN compared to TACE alone, which further reduces recurrence risk. Comparative studies of transarterial radioembolization (TARE, including Y-90) with TACE and surgical resection indicated that while recurrence rates, OS, and progression times were not significantly different, TARE required fewer treatment sessions, shorter hospital stays, and resulted in fewer arterial complications and adverse events[37-39].

In conclusion, for patients with the financial resources, Y-90 offers a promising alternative to traditional treatments, providing improved therapeutic options for liver cancer with more favorable outcomes and better patient quality of life.

ROLE OF TARGETED THERAPY IN HCC TREATMENT AND RECURRENCE CONTROL

The application of targeted therapy in liver cancer primarily revolves around precise interventions targeting specific molecular mechanisms within tumor cells. Following the regulatory approval of sorafenib in 2007 as the inaugural targeted agent for advanced HCC, the therapeutic paradigm for systemic management of hepatic malignancies underwent a transformative evolution. The success of sorafenib not only offered new therapeutic options for patients but also spurred the development of multi-kinase inhibitors, antiangiogenic agents, and immune checkpoint inhibitors (ICIs). In recent years, the approvals of lenvatinib and regorafenib have further advanced the efficacy and safety of targeted therapies in HCC management, underscoring significant progress in the field (Table 2).

Table 2 The mechanism of action of targeted therapy, efficacy in hepatocellular carcinoma recurrence, main limitations and relevant improvement strategies.

Type	Treatment	Mechanism	Efficacy	Limitations	Strategies	Ref.
First-line treatment; Second-line treatment	Sorafenib	Inhibit VEGFR, PDGFR-β, and the RAF/MEK/ERK pathway	Sorafenib significantly improved the median overall survival (10.7 months vs 7.9 months; P < 0.001) and radiographic progression-free survival (5.5 months vs 2.8 months; P < 0.001) in patients with advanced HCC	The use of sorafenib as monotherapy in adjuvant treatment and the prevention of HCC recurrence after surgery has no significant efficacy	TACE + sorafenib/TACE + sorafenib + radiotherapy; Switch to other effective medications	Wilhelm et al[40];Rimassa and Santoro[41];Bruix et al[42];Li et al[43];Jiang et al[44];Peng et al[45];Fan et al[46]
	Lenvatinib	Inhibit VEGFR 1-3, FGFR 1-4, PDGFR-α, RET and KIT	Lenvatinib has a superior ORR compared to sorafenib in HCC; The median overall survival in the lenvatinib group for the treatment of recurrent hepatocellular carcinoma after liver transplantation was significantly longer (15.0 months vs 7.8 months, P = 0.02)	Individual differences and resistance exist	TACE + lenvatinib/pembrolizumab + lenvatinib; Switch to other effective medications	Yamamoto et al[48]; Al-Salama et al[49]; Kudo et al[51]; Magyar et al[52];Peng et al[53];Liang et al[54];Zhang et al[55];Lv et al[56]
Second-line treatment	Regorafenib	Inhibit VEGFR1-3, TIE2, FGFR, PDGFR-β, KIT, RET and p38MAPK/Creb1/Klf4	Regorafenib has demonstrated good anti-tumor activity and effectively prolonged survival in HCC patients who experienced recurrence or progression after sorafenib treatment	Severe toxic side effects with a high incidence	Adopt a stepwise dosing strategy	Eso and Marusawa[58]; Ou et al[59]; Bruix et al[60]; Bruix et al[61]; Finn et al[62]; Bekaii-Saab et al[63]
	Cabozantinib	Inhibit VEGFR1-3, MET and AXL	The phase III clinical trial was positive, with an overall ORR of 4%	The overall efficacy is limited	Cabozantinib + nivolumab; Screening for sensitive patients	Argentiero et al[64]; Abou-Alfa et al[65]; Yang et al[66]

VEGFR: Vascular endothelial growth factor receptor; PDGFR: Platelet-derived growth factor receptor; FGFR: Fibroblast growth factor receptor; TIE2: Angiopoietin-1 receptor; MAPK: Mitogen-activated protein kinase; ORR: Objective response rate; HCC: Hepatocellular carcinoma; TACE: Transarterial chemoembolization.

Sorafenib

Sorafenib, a multi-kinase inhibitor, is widely used clinically. It inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor-β (PDGFR-β), and the mitogen-activated protein kinase/extracellular regulated protein kinases signaling pathway, effectively suppressing tumor cell proliferation and angiogenesis[40]. The SHARP trial demonstrated that sorafenib significantly improved median OS (10.7 vs 7.9 months; P < 0.001) and PFS (5.5 vs 2.8 months; P < 0.001) in patients with advanced HCC[41]. A subsequent Asia-Pacific phase III trial also showed that sorafenib significantly prolonged OS and PFS in patients with advanced HCC, with good tolerability. Median OS increased from 4.2 to 6.5 months (P = 0.014), and PFS from 1.4 to 2.8 months (P = 0.0005)[42], further supporting the findings of the SHARP trial.

Despite its significant role in advanced HCC, sorafenib monotherapy after HCC resection has not shown satisfactory results in adjuvant therapy and recurrence prevention. The STORM trial found no significant difference in recurrence-free survival (RFS) or OS between the sorafenib and placebo groups[42]. However, this does not negate sorafenib’s potential. Recent studies suggest that combination therapies incorporating sorafenib hold promise.

TACE has demonstrated significant clinical benefits in the treatment of HCC. However, post-TACE treatment leads to the upregulation of hypoxia-inducible factor-1 alpha, VEGF, and PDGF expression, resulting in increased tumor vascularization and subsequently higher postoperative recurrence rates[43]. Sorafenib, by contrast, can reduce the vascular density of HCC, thereby compensating for this limitation, prolonging patient survival, and reducing recurrence[44]. Consequently, increasing attention has been directed towards the combined use of TACE and sorafenib. A Chinese multicenter phase III randomized clinical trial demonstrated that adjuvant sorafenib combined with TACE significantly improved RFS [16.8 (12.0-NA) vs 12.6 (7.8-18.1) months; HR = 0.57; 95%CI: 0.39-0.83; P = 0.002] and OS [30.4 (20.6-NA) vs 22.5 (15.4-NA) months; HR = 0.57; 95%CI: 0.36-0.91; P = 0.02] compared to sorafenib alone in patients with HCC and PVTT after surgery[45]. Another phase III trial in patients with intermediate-stage HCC recurrence after R0 resection with MVI showed that sorafenib combined with TACE significantly improved median OS (22.2 vs 15.1 months; HR = 0.55; P < 0.001), PFS (16.2 vs 11.8 months; HR = 0.54; P < 0.001), and objective response rate (ORR) (80.2% vs 58.0%; P = 0.002) compared to TACE alone[46]. These findings suggest that combination therapies incorporating sorafenib hold considerable potential for improving outcomes in patients with high-risk or recurrent HCC. Additionally, compared to prior studies, the TACTICS trial demonstrated that differences in the median duration of sorafenib treatment contributed to improved outcomes[47]. This highlights the need for further investigation into key parameters including the sequencing, timing intervals, and optimal dosing of TACE-sorafenib combination therapy.

Lenvatinib

Lenvatinib is an oral multi-target tyrosine kinase inhibitor primarily targeting VEGFRs 1-3 and fibroblast growth factor receptors (FGFRs 1-4) while also inhibiting other signaling pathways such as PDGFR-α, RET, and KIT[48,49]. Recent research indicates that lenvatinib induces ferroptosis in HCC cells by inhibiting FGFR4. Lenvatinib demonstrates greater efficacy in patients with high FGFR4 expression compared to those with low expression in recurrent HCC, and patients with FGFR4-positive HCC exhibit significantly longer PFS than those with FGFR4-negative HCC[50]. Overall, lenvatinib exhibits significant anti-tumor activity by inhibiting tumor angiogenesis and tumor cell proliferation while inducing ferroptosis.

Approved in 2018 based on a phase III noninferiority trial, lenvatinib is a first-line treatment for advanced or unresectable HCC, alongside sorafenib, offering a new option for prolonging survival in patients with advanced HCC[51]. Compared to sorafenib, lenvatinib demonstrates a higher ORR, and a study on HCC recurrence after LT reported significantly longer median OS in the lenvatinib group (15.0 vs 7.8 months, P = 0.02)[51,52]. Thus, lenvatinib is considered superior to sorafenib in managing HCC recurrence.

Combination therapies are a major focus for improving efficacy. A multicenter phase III clinical trial from 12 hospitals in China showed that combining lenvatinib with TACE significantly improved median OS (17.8 vs 11.5 months), PFS (10.6 vs 6.4 months), and ORR (54.1% vs 25%) while maintaining safety[53]. Another study in patients with MVI-positive HCC supports this finding, where TACE plus lenvatinib resulted in superior OS and PFS compared to TACE or lenvatinib alone[54]. This synergy suggests that TACE’s tumor debulking effect, combined with lenvatinib’s antiangiogenic and anti-proliferative effects, effectively reduces recurrence and metastasis. Similar results were observed with sorafenib but with comparable adverse effects; the combination of TACE and lenvatinib demonstrated superior disease control rates and median OS compared to TACE plus sorafenib[55].

LT offers a potential cure for HCC, but the recurrence risk and strict selection criteria limit its applicability. A randomized trial of neoadjuvant pembrolizumab plus lenvatinib showed that this regimen, administered before LT in patients exceeding the Milan criteria and with high u-stage scores, effectively reduced post-transplant recurrence[56]. Overall, lenvatinib-based combination therapies outperform sorafenib in improving patient survival, controlling recurrence, and offering new avenues for neoadjuvant therapy in HCC.

Other targeted therapies

Regorafenib is a multi-kinase inhibitor, and the first systemic therapeutic agent demonstrated to be effective against HCC following sorafenib treatment[57]. Its targets are diverse and encompass key pathways involved in tumor progression, including VEGFR1-3, angiopoietin-1 receptor, FGFR, PDGFR-β, and genes related to oncogenic kinases, such as KIT and RET[58]. Besides its antiangiogenic effects, regorafenib enhances M1 macrophage polarization and anti-tumor immunity by inhibiting the p38 mitogen-activated protein kinase/Creb1/Klf4 signaling pathway in tumor-associated macrophages (TAMs)[59].

More than a decade ago, studies established the anti-tumor efficacy of regorafenib in patients with HCC who experienced recurrence or progression following sorafenib treatment[60]. Subsequently, a larger, international, multicenter phase III clinical trial concluded that regorafenib remains the only systemic treatment proven to extend survival in patients with HCC progression after sorafenib therapy[61]. Recent studies further support the sequential use of sorafenib followed by regorafenib, demonstrating meaningful survival extension in patients with HCC[62]. However, severe adverse effects currently limit the clinical application of regorafenib. Evidence from a study on metastatic colorectal cancer suggested that a stepwise dose-escalation strategy could effectively reduce the occurrence of adverse events associated with the standard dose without compromising efficacy[63]. This provides a potential avenue for future research into mitigating regorafenib’s toxicity in the treatment of recurrent HCC.

Cabozantinib, another multi-kinase inhibitor, targets VEGFR1-3, MET, and AXL-key targets implicated in HCC progression and resistance to sorafenib. These pathways play critical roles in HCC recurrence[64]. Although results from a phase III clinical trial were positive, the ORR was only 4%[65]. A case report involving a 71-year-old male with metastatic HCC illustrated cabozantinib’s potential when used in combination therapies. In this case, genetic testing revealed RET amplification, high tumor mutational burden, and elevated programmed cell death ligand 1 (PD-L1) expression. Notably, the combination of cabozantinib and nivolumab yielded observable therapeutic effects within 2 months, and near-complete resolution of the metastatic lesion was achieved after 10 months of treatment[66]. Future studies are warranted to further elucidate cabozantinib’s mechanism of action, optimize its clinical application, and establish more precise molecular classification and stratification in clinical trials to better evaluate its efficacy.

ROLE OF IMMUNOTHERAPY IN HCC TREATMENT AND RECURRENCE CONTROL

Immunotherapy and the tumor microenvironment

Immunotherapy represents a novel strategy in HCC, designed to activate or enhance the patient’s immune system to recognize and attack cancer cells. Its efficacy is closely linked to the tumor microenvironment (TME), a complex ecosystem comprising tumor cells, immune cells, stromal cells, blood vessels, and extracellular matrix. Immune cells, broadly categorized into innate and adaptive immune cells, are the key players in the TME[67]. Dendritic cells (DCs) are a bridge between innate and adaptive immunity. As a quintessential representative of antigen-presenting cells, they activate T cell-mediated tumor cytotoxicity through antigen presentation[68]. A recently identified immunostimulatory cDC1 subset (MHCII^hiCCR7^neg cDC1) not only engages in classical antigen presentation but also facilitates cluster of differentiation (CD) 8 + T cell activation and expansion via two independent mechanisms: Direct antigen presentation and secretion of the chemokines CXCL9 and CXCL10 to recruit CD8 + T cells[69]. Natural killer (NK) cells constitute a vital component of innate immunity. They mediate tumor cell killing through both direct mechanisms, such as the release of cytotoxic molecules, and indirect pathways involving the activation of other immune cells. Furthermore, NK cells can execute antibody-dependent cell-mediated cytotoxicity[70]. Jia et al[71] demonstrated that SPON2 + NK cells not only exhibit elevated expression of interferon (IFN)-γ and perforin, conferring robust direct cytotoxic activity against tumor cells, but also engage in reciprocal interactions with CD8 + T cells. This crosstalk may potentiate the anti-tumor immunity of CD8 + T cells, consequently mitigating tumor progression and relapse. Building upon the functional and spatial attributes of SPON2 + NK cells in the TME, the authors subsequently devised a predictive assay for HCC recurrence risk[71]. Among adaptive immune cells, CD8 + T cells are the primary effectors. They recognize tumor antigens via the T-cell receptor and induce direct tumor cell lysis by secreting perforin and granzyme B, which trigger apoptosis in target cells[72]. However, the elevated expression of immune checkpoint molecules, including programmed cell death protein 1 (PD-1)/PD-L1 on tumor cells and TAMs, increase of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and the newly discovered immune checkpoint T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3), suppresses T cell proliferation and activation, ultimately resulting in their dysfunction and exhaustion[73].

In a word, the TME plays an irreplaceable role in HCC initiation, progression, metastasis, and recurrence[74]. The TME often exhibits an immunosuppressive phenotype, characterized by the accumulation of TAMs, regulatory T-cells (Tregs), and immunosuppressive cytokines, along with abnormal angiogenesis, chronic inflammation, and extracellular matrix remodeling dysregulation. This frequently leads to impaired immune cell function, diminishing immunotherapy’s effectiveness[75].

To address this challenge, various immunotherapies have been developed, including ICIs to counteract immunosuppression and enhance T-cell-mediated tumor killing[76]; adoptive cell therapies involving in vitro modification or expansion of immune cells for targeted tumor attack[77]; therapeutic vaccines to activate specific anti-tumor immune responses; and cytokine therapies to modulate immune system function and suppress tumor growth[78]. These approaches, when used alone or in combination with other therapies, offer new treatment options for patients with HCC (Table 3).

Table 3 The mechanism of action of immunotherapy, efficacy in hepatocellular carcinoma recurrence, main limitations and relevant improvement strategies.

Type	Treatment	Mechanism	Efficacy	Limitations	Strategies	Ref.
ICIs	PD-1/PD-L1 inhibitors	Inhibiting PD-1/PD-L1 weakens the suppression of T cells by cancer cells	The results of the CheckMate 040 and KEYNOTE-224 trials showed that nivolumab and pembrolizumab significantly improved ORR, OS, and PFS in HCC	Drug resistance and individual population differences	Atezolizumab + bevacizumab/nivolumab + ipilimumab	El-Khoueiry et al[81];Zhu et al[82];Qin et al[85];Finn et al[86]
	TIM3-targeted therapy	Blocking the binding of TIM-3 to its ligand reduces its inhibition of immune cells	Higher expression of TIM-3L is often associated with shorter survival and a higher likelihood of recurrence	The complexity of the microenvironment	Radiotherapy + immunotherapy + AZD6738	Yang et al[88]; Wang et al[89]; Khan et al[90]; Chew et al[91]; Kim et al[92]; Li et al[93]; Cheng et al[94]; Chen et al[95]; Sheng et al[96]
Adoptive cell therapy	TILs	T cells extracted from tumor tissue are expanded in vitro and reinfused	In a phase I clinical trial involving 15 HCC patients, only 3 patients experienced recurrence after a median follow-up of 14 months	The current clinical trials have small sample sizes and lack higher-phase clinical trials	Further clinical trials and studies on combination therapy	Jiang et al[99]; Liu et al[100]
	CAR-T	Modify, expand and reinfuse T cells	GPC3 T cell therapy for GPC3-positive advanced hepatocellular carcinoma patients has shown a significant decrease in AFP levels and prolonged survival in some patients	Adverse events are common, and the clinical benefits for solid tumors remain unclear	Monitor adverse events, especially to prevent CRS; Identify more effective therapeutic targets	Maalej et al[101];Jiang et al[102];Beatty et al[103]; Ruella and Kalos[104]; Shi et al[105]
	NK cell therapy	Modify, expand and reinfuse NK cells	Multiple allogeneic NK cells infusion was associated with better prognosis to advanced HCC	The limited availability of mature NK cell sources and the restricted efficacy of single-agent NK therapy remain challenges	NK cells can be generated by culturing CD34 + stem cells, and combination therapies, such as NK cells combined with chemotherapy	Cai et al[106]; Lin et al[107]; Ohira et al[108]
Tumor vaccines	DNA vaccines	Introduce the DNA encoding tumor-associated antigens into the host cell nucleus	A total of 36 patients with advanced HCC underwent combination therapy with PTCV, PD-1 inhibitors, and IL-2. The ORR reached 30.6%, with 8.3% of patients achieving complete remission	Limited efficacy as a standalone treatment; Low bioavailability; Risk of unintended integration of foreign genetic material into the host cell genome	Combine with other immunotherapies; Use nanocarriers/RBC-nano-vaccines for targeted delivery; Replace with mRNA vaccines	Rice et al[112]; Butterfield et al[113]; Wu et al[114]; Hobernik et al[105]; Yarchoan et al[116]
	mRNA vaccines	Introduce the mRNA encoding tumor-associated antigens into the host cell cytoplasm	The combination of pembrolizumab and mRNA-4157 significantly reduces the recurrence rate in patients with high-risk melanoma	Limited efficacy as a standalone treatment; Low bioavailability	Combine with other immunotherapies; Use lipid nanoparticles for delivery	Cagigi and Douradinha[117]; Huang et al[118];Weber et al[119]
Cytokine therapy	IL-2, IFN	Enhance the body’s anti-tumor immune response	After IL-2 treatment, the survival rate of unresectable HCC patients increased; IFN can reduce the mortality and early recurrence rates of HCC patients after curative treatment	Severe side effects and the inability to accumulate sufficiently effective drug concentrations within the tumor	Search for new or artificially modified cytokines and further studies on combination therapy	Bertelli et al[120];Zhang et al[121]; Charych et al[122]; Walker et al[123]

ICIs: Immune checkpoint inhibitors; IFN: Interferon; IL-2: Interleukin-2; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death ligand 1; TIM3: T-cell immunoglobulin and mucin domain-containing molecule 3; TILs: Tumor-infiltrating lymphocytes; CAR-T: Chimeric antigen receptor-T; NK: Natural killer; mRNA: Message RNA; ORR: Objective response rate; HCC: Hepatocellular carcinoma; OS: Overall survival; RFS: Recurrence-free survival; GPC3: Chimeric antigen receptor-glypican-3; AFP: Alpha-fetoprotein; PTCV: Personalized neoantigen cancer vaccine; CRS: Cytokine release syndrome; CD: Cluster of differentiation; RBC: Red blood cell.

Despite tumor cell heterogeneity, the TME exhibits notable consistency across patients. Single-cell RNA-seq analysis of human liver TMEs supports this, revealing that despite high variability in cancer cells, gene expression profiles within the liver TME remain relatively stable across individuals. Furthermore, recurring ligand-receptor interactions between tumor and stromal cells were identified, and were also consistent across patients[79]. This molecular-level reproducibility in the HCC TME provides a basis for immunotherapy. However, the TME differs between primary and recurrent HCC. Single-cell sequencing of early recurrent HCC revealed significant differences in the immune microenvironment compared to primary HCC (PT). Early recurrent HCC (RT) showed a reduced proportion of Tregs but increased proportions of DCs and CD8 + T-cells. However, CD8 + T-cells in RT exhibited an innate-like phenotype with low cytotoxicity and clonal expansion, unlike the typical exhausted state in PT. Furthermore, malignant cells in RT display enhanced immune evasion capabilities, potentially suppressing DC activation of CD8 + T-cells, leading to a poorer prognosis and potentially contributing to HCC recurrence[80] (Figure 1).

Figure 1 Treatment and high-risk factors for hepatocellular carcinoma recurrence and changes in the tumor microenvironment. Radiotherapy, targeted therapy and immunotherapy have played significant roles in the treatment of hepatocellular carcinoma (HCC) recurrence. However, portal vein tumor thrombus, large tumor size, multiple tumors and incomplete treatment can significantly increase the risk of HCC recurrence. In the immune microenvironment of recurrent liver cancer, there are many changes. There is an increase in immune checkpoint expressions [e.g., programmed cell death protein 1/programmed cell death ligand 1, T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3)/TIM-3 L, cytotoxic T-lymphocyte-associated protein-4], a rise in the proportion of dendritic cells, and a decrease in the proportion of regulatory T-cells. Although the proportion of T cells remains elevated, these T cells become exhausted T cells, exhibited an innate-like phenotype with low cytotoxicity and clonal expansion. PVTT: Portal vein tumor thrombus; HCC: Hepatocellular carcinoma; TME: Tumor microenvironment; DC: Dendritic cell; Tregs: Regulatory T-cells; TIM: T-cell immunoglobulin and mucin domain-containing molecule; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death ligand 1; CTLA4: Cytotoxic T-lymphocyte-associated protein-4; CD: Cluster of differentiation.

ICIs

ICIs are key regulatory molecules expressed by immune cells, playing a crucial role in maintaining self-tolerance and regulating immune responses. These molecules hold significant promise in cancer treatment, particularly for HCC. Key targets include PD-1 and PD-L1, TIMs, and other lymphocyte inhibitory factors. The high recurrence rate and limited treatment options for HCC have made immunotherapy a major area of research.

PD-1/PD-L1 inhibitors: The CheckMate 040 and KEYNOTE-224 trials demonstrated that nivolumab and pembrolizumab significantly improved ORR, OS, and PFS in HCC, leading to their Food and Drug Administration approval as PD-1/PD-L1 inhibitors[81,82]. Although nivolumab exhibits good clinical activity and safety in advanced HCC, its overall efficacy in preventing recurrence remains limited, with challenges related to drug resistance and inter-patient variability. The CheckMate 459 trial showed no significant improvement in median OS with nivolumab compared to sorafenib[83]. These limitations of single PD-1/PD-L1 inhibitor therapy have prompted research into combination strategies. These include combining with anti-angiogenic therapies and other ICIs to enhance efficacy and reduce recurrence.

Anti-angiogenic agents inhibit VEGF and its signaling pathways, blocking tumor angiogenesis. This deprives tumors of blood supply and indirectly modulates the TME’s immune status[84]. Bevacizumab is a commonly used anti-VEGF monoclonal antibody. The IMbrave 050 trial, involving 668 high-risk patients with HCC post-resection or ablation, showed that atezolizumab + bevacizumab significantly prolonged RFS in the adjuvant setting (HR = 0.72, P = 0.012) at a median follow-up of 17.4 months[85]. The Imbrave 150 trial demonstrated that atezolizumab + bevacizumab significantly improved median PFS compared to sorafenib (6.8 vs 4.5 months, HR = 0.59, 95%CI: 0.47-0.76; P < 0.001) with comparable adverse events[86]. Consequently, this combination is now approved as a standard first-line treatment for unresectable HCC.

Combination immunotherapy also shows promise. CTLA-4 inhibitors, by blocking CTLA-4 binding to its ligand, disinhibit T-cell activation and enhance anti-tumor immunity. In HCC, CTLA-4 inhibitors (e.g., ipilimumab) are often combined with PD-1/PD-L1 inhibitors (e.g., nivolumab). Compared to nivolumab monotherapy, nivolumab + ipilimumab showed better ORR and more durable responses in sorafenib-pretreated patients with HCC[87].

TIM3-targeted therapy: TIM-3, a type I transmembrane protein of the TIM family, is expressed on terminally differentiated T-cells, Th17 cells, NK cells, and monocytes. Recently, TIM-3 has emerged as a promising immune checkpoint target in HCC treatment. Initially believed to mediate T-cell apoptosis via binding to its ligand galectin-9[88], classified as TIM-3 L, which also interact with TIM-3 and modulate immune function. Multiplex immunofluorescence studies have revealed a positive correlation between TIM-3 and TIM-3 L expression in the HCC TME, with higher TIM-3 L expression associated with shorter survival and increased recurrence risk[89]. However, the role of the TIM-3 target in the TME is complex; it not only affects T-cell function but also collaborates with other immune suppressive molecules like PD-1 and lymphocyte activation gene-3 to promote immune evasion[90]. Thus, single TIM-3-targeted therapy may not be sufficient to fully reverse the immunosuppressive state of the TME.

Radiotherapy, in addition to its direct cytotoxic effect on tumor cells, is increasingly recognized for its ability to activate the immune system and alter the TME. For instance, in patients treated with Y-90, increased infiltration of immune cells such as CD8 + T-cells and CD56 + NK cells, along with upregulation of immune activation-related genes, are observed locally. Systemically, increased tumor necrosis factor-α production in peripheral blood mononuclear cells and a higher proportion of antigen-presenting cells are also observed[91]. Local irradiation recruits CD4 + T-cells mediating TIM-3 function to the Hca-1 tumor and upregulates TIM-3 expression in a time-dependent manner[92]. Combination therapy with radiotherapy and immunotherapy has demonstrated good safety profiles and promising efficacy in HCC. The notable-HCC trial is a phase 1b study investigating tislelizumab combined with SBRT as a neoadjuvant treatment in early-stage resectable HCC. Among the enrolled patients, the ORR was 63.2%, and 10.5% of patients achieved complete pathological response. While ensuring safety, this regimen significantly enhanced tumor response in early-stage resectable HCC[93].

The combination of radiotherapy, immunotherapy, and DNA damage response (DDR) inhibitors has gradually gained attention. DDR inhibitors play a dual role in this treatment. On one hand, DDR inhibitors directly enhance the efficacy of radiotherapy by inhibiting DNA repair mechanisms in tumor cells[94], thereby intensifying radiation-induced DNA damage. On the other hand, DDR inhibitors can relieve the suppression of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway by the RNA helicase RECQL4, thereby promoting DC antigen presentation, activating CD8 + T cells, and enhancing type I IFN release[95]. This multi-faceted mechanism comprehensively amplifies the immunostimulatory effects of radiotherapy. AZD6738, a representative DDR inhibitor, when combined with radiotherapy and immunotherapy in a mouse model, significantly improved CR rates and survival compared to radiotherapy or radioimmunotherapy alone. This triple combination therapy significantly increased the percentage of central memory T-cells, demonstrating an advantage in treating secondary tumors and preventing recurrence[96]. This finding suggests that combined radio-immunotherapy holds significant promise.

In addition, biomaterials are being increasingly integrated into TIM-3 research to improve drug delivery. A novel potential of hydrogen-sensitive nanoparticle drug delivery system enables the targeted co-delivery of TIM-3 siRNA and sorafenib to the liver tumor site, significantly inhibiting tumor growth via TIM-3 knockdown and the synergistic effects with sorafenib[97]. Another study developed biomimetic anti-tumor nanoparticles (BAT NPs) by coating poly (lactic-co-glycolic acid) nanoparticles with platelet membranes and loading them with TIM-3 and PD-L1 antibodies. These BAT NPs reverse the immunosuppressive microenvironment in HCC, combining the effects of two ICIs while also promoting T-cell proliferation and migration and inducing tumor starvation via collagen deposition, thus prolonging survival[98].

Although clinical studies on TIM-3 remain limited, preclinical and animal model studies suggest significant therapeutic potential for this novel immune checkpoint in treating HCC and preventing recurrence.

Adoptive cell therapy

Adoptive cell immunotherapy mainly encompasses tumor-infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR)-T-cell therapy, and NK cell therapy, which specifically target and kill tumors.

TILs are T-cells extracted from tumor tissue with natural tumor-recognition capabilities. A phase I clinical trial demonstrated that this therapy is associated with low-grade adverse events and good safety. Among 15 patients in the trial, only three experienced recurrence after a median follow-up of 14 months[99]. A case report described a 75-year-old patient with advanced HCC who received neoantigen-reactive T-cell immunotherapy in combination with radiotherapy, apatinib plus a PD-1 antibody, followed by PD-1 monotherapy. This regimen resulted in tumor shrinkage, decreased tumor markers, and subsequent PR in a portal vein lesion and CR in a left lateral segment lesion[100]. This successful treatment highlights the potential of cell therapy, particularly in combination therapies for HCC and recurrence prevention.

In recent years, CAR-T-cell therapy has demonstrated remarkable efficacy in the treatment of hematologic malignancies[101]. While breakthroughs in using CAR-T-cell therapy to control solid tumors like HCC are yet to be achieved, early clinical trials targeting antigens such as Claudin 18.2 (CA125)[102], mesothelin[103], and IL13Rα2 have shown promising anti-tumor activity. These findings suggest the potential feasibility of CAR-T-cell therapy for solid tumors. Overall, this therapy has shown good tolerability, with common side effects including fever, lymphopenia, and cytokine release syndrome[104]. A phase I clinical trial assessing the efficacy of CAR-glypican-3 (GPC3) T-cell therapy in patients with advanced GPC3-positive HCC revealed heterogeneity in outcomes among the 13 participants. However, some exhibited significant reductions in alpha-fetoprotein (AFP) levels and extended survival, providing preliminary evidence of its potential benefits[105]. Although clear clinical benefits have not yet been achieved, this result still reinforces our confidence in the prospects of CAR-T therapy in the treatment of liver cancer and its recurrence.

NK cells play a vital role in immune surveillance against liver cancer by directly targeting tumor cells, modulating the TME, and enhancing anti-cancer immune responses. Both the number and function of NK cells are significantly reduced in patients with HCC, highlighting their importance in liver cancer immunity[106]. Studies have reported a positive correlation between multiple infusions of allogeneic NK cells and improved clinical outcomes in advanced HCC cases[107]. A phase I clinical trial in Japan explored the use of CD34 + stem cell-derived NK cells for treating high-recurrence HCC. Although the trial is ongoing, it has addressed the limitations of insufficient numbers of mature NK cells by using non-liver-derived NK cells. This approach offers new potential for preventing and treating recurrent HCC[108].

Additionally, chemotherapy has been found to enhance NK cell activity, upregulate UL16-binding protein 2, and reduce the function of myeloid-derived suppressor cells and Tregs, thereby amplifying NK cell-mediated tumor immunity[109,110]. Recent advancements include a phase I open-label clinical trial assessing the combination of high-dose localized NK cell infusion with hepatic artery infusion chemotherapy for advanced HCC. This study demonstrated both the safety and efficacy of the approach, achieving an ORR of 63.6%[111]. This further validates the importance of the synergistic effects of multiple therapies in liver cancer treatment.

Currently, research on adoptive cell immunotherapy for liver cancer is actively exploring strategies to optimize cell culture, enhance cell activity, and overcome immune suppression to improve efficacy and patient outcomes. Larger-scale clinical trials are still needed to validate its efficacy and safety, as well as to investigate ways to further enhance treatment durability and reduce side effects. The development of safer gene-editing technologies and the identification of novel tumor-specific antigens to improve the precision and effectiveness of treatment are also possible areas of interest.

Tumor vaccines

Tumor vaccines have garnered significant attention for their ability to specifically activate the immune system to kill cancer cells. Among the various candidate vaccines, DNA vaccines have demonstrated great potential in liver cancer treatment due to their high stability, ease of production, and capacity to elicit a sustained antigen-specific immune response[112]. However, using DNA vaccines alone is challenging due to large molecular size, high negative charge, and susceptibility to degradation, which reduce their bioavailability and lead to suboptimal immune responses. These issues can be addressed through the use of nanoscale delivery carriers[113]. Recent studies have found that utilizing red blood cell-nano-vaccines for targeted delivery to the spleen enhances the uptake of DNA vaccines by antigen-presenting cells and other immune cells, significantly improving their immunogenicity[114]. Nonetheless, DNA vaccines alone still face numerous challenges and have not demonstrated substantial clinical benefits[115]. However, their role in augmenting the efficacy of other immunotherapies cannot be overlooked. A phase I/II single-arm clinical trial involving 36 patients with advanced HCC employed a combination therapy of personalized cancer vaccine, PD-1 inhibitor, and interleukin-2 (IL-2) and achieved an ORR of 30.6%, with 8.3% of patients achieving complete remission[116].

The corona virus disease 2019 pandemic brought message RNA (mRNA) vaccines into the spotlight. Unlike DNA vaccines, mRNA vaccines are directly translated into the cytoplasm, eliminating the risk of unintentional integration of foreign genetic material into the host cell genome[117], resulting in greater safety and a more rapid immune response. However, similar to DNA vaccines, single mRNA vaccines face certain challenges[118], making combination therapies the preferred approach. A combination of pembrolizumab and a lipid nanoparticle-formulated mRNA cancer vaccine encoding multiple neoantigens (mRNA-4157) has been tested as an adjuvant therapy for patients with high-risk cutaneous melanoma, demonstrating significant clinical outcomes in reducing recurrence rates[119]. Although research on mRNA vaccines for liver cancer is still in its infancy, these findings provide a promising framework for studying mRNA vaccines in the context of liver cancer recurrence.

Cytokine therapy

Cytokine therapies, such as IL-2 and IFN, can enhance the immune response by either directly targeting tumor cells or suppressing tumor growth. IL-2 promotes T-cell proliferation and activates its anti-tumor activity. In patients with unresectable HCC, IL-2 therapy has been associated with improved survival rates[120]. A meta-analysis further revealed that adjuvant IFN, when used after curative treatment for HCC, significantly reduced mortality and early recurrence rates. However, the effects of IFN vary among patients with different underlying etiologies[121], highlighting the need to tailor adjuvant IFN therapy according to the specific background of HCC. Despite its potential, the efficacy of cytokine therapy in HCC has been inconsistent, largely due to significant side effects and suboptimal tumor concentrations achieved by traditional cytokine therapies, which limit their clinical application. Bempegaldesleukin (NKTR-214), a CD122-biased IL-2 pathway agonist, offers promising advancements over conventional IL-2. It extends the drug’s half-life, selectively activates CD8 + T-cells and NK cells, and demonstrates reduced toxicity while enhancing therapeutic efficacy[122]. Preclinical studies have shown that combining NKTR-214 with high-dose radiotherapy effectively stimulates systemic tumor immunity, leading to improved outcomes in locally advanced and metastatic cancers compared to cytokine monotherapy. This combination strategy holds significant potential for advancing cancer immunotherapy approaches[123].

Nevertheless, cytokines also play a role in recurrence prevention. A study reviewing data from 150 patients with HCC who underwent LT between 1997 and 2015 found that circulating CCL11, IFN-α2, and IL-17A levels post-transplant were key predictors of recurrence and survival. A new predictive score (P3C-UCSF-AFP score) was developed based on these cytokines, UCSF criteria, and preoperative AFP levels. This score showed better predictive accuracy than existing models, effectively differentiating patients at different risk levels and improving survival rates in high-risk patients[124].

CONCLUSION

High recurrence rates in HCC significantly worsen patient prognosis. Current treatments such as surgery, transplantation, and ablation are effective in early-stage patients, but their efficacy is limited in advanced or recurrent cases. This review summarizes the roles of radiotherapy, targeted therapy, and immunotherapy in managing postsurgical HCC recurrence and explores the importance of TME in HCC recurrence mechanisms. While advancements in targeted therapies, such as lenvatinib and ICIs have improved treatment outcomes, further research is needed to optimize treatment strategies, such as improving drug dosage regimens and combination therapies, to enhance efficacy and reduce recurrence. Tumor vaccines and cytokine therapies show potential but are still in the early stages of development and require further investigation to validate their efficacy and safety. Future research should focus on a deeper understanding of HCC recurrence mechanisms, the identification of more effective therapeutic targets, and development of novel combination treatment strategies to ultimately improve patient outcomes.