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

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.