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. 2026 Jun 23;32:e953528. doi: 10.12659/MSM.953528

A Review of Recent Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapy for Hepatocellular Carcinoma

Xiaopan Lv 1,A,B,E,*, Xuemei Chen 1,B,C,E,*, Yuxin Ge 1,A,C, Guifei Si 1,D,F, Yuquan Li 1,B,C,D, Xiuping Li 2,D,F, Xuemin Yuan 2,A,C,F,G,✉
PMCID: PMC13309999  PMID: 42332855

Abstract

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and poses a major global health burden. It remains a leading cause of cancer-related death worldwide, with persistently high incidence and mortality in regions affected by chronic viral hepatitis, cirrhosis, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease.

Although surgical resection, liver transplantation, locoregional therapies, molecular targeted agents, and immune checkpoint inhibitors have improved treatment options, outcomes for advanced HCC remain unsatisfactory. Chimeric antigen receptor (CAR) T-cell therapy is an adoptive cellular immunotherapy in which T lymphocytes are genetically engineered to recognize tumor-associated antigens and eliminate malignant cells. CAR-T-cell therapy has achieved major clinical success in hematologic malignancies, but its application in HCC is still developing because of tumor heterogeneity, antigen escape, limited T-cell trafficking, and an immunosuppressive tumor microenvironment. Recent studies have investigated several HCC-associated targets, including glypican-3 (GPC3), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), CD133, epidermal growth factor receptor variant III (EGFRvIII), B7 homolog 3 (B7H3), mucin 1 (MUC1), natural killer group 2 member D ligand (NKG2DL), programmed death-ligand 1 (PD-L1)/c-Met, CD147, CD44, and epithelial cell adhesion molecule (EpCAM). This article provides a target-oriented synthesis of HCC-related CAR-T-cell therapy, summarizes registered clinical studies according to antigen target, CAR design, trial phase, administration route, and available outcomes, and discusses how CAR structural evolution may influence therapeutic development in HCC. This article aims to review recent advances in CAR-T-cell therapy for hepatocellular carcinoma.

Keywords: Carcinoma, Hepatocellular; Receptors, Chimeric Antigen; T-Lymphocytes; Immunotherapy, Adoptive; Review

Introduction

Hepatocellular carcinoma (HCC) is the predominant histologic subtype of primary liver cancer and represents a substantial global health burden [1–4]. Liver cancer remains among the leading causes of cancer-related death worldwide, and HCC accounts for most primary liver cancer cases [3–6]. The incidence and mortality of HCC remain high in regions with prevalent chronic hepatitis virus infection, cirrhosis, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease [4,7,8].

Curative-intent treatments for early-stage HCC include surgical resection, local ablation, and liver transplantation [9–11]. However, many patients are diagnosed at an advanced stage or have underlying chronic liver disease that limits curative treatment options [4,7,8,12]. Systemic treatment has evolved from sorafenib to several targeted agents and immune checkpoint inhibitor-based strategies, including regorafenib, lenvatinib, cabozantinib, ramucirumab, pembrolizumab, and nivolumab [13–25]. Despite these advances, durable responses remain limited in many patients with advanced HCC, supporting the need for new therapeutic approaches [20,23–25].

Chimeric antigen receptor (CAR) T-cell therapy is a form of adoptive cellular immunotherapy in which T cells are genetically modified to express synthetic receptors that recognize tumor-associated antigens independently of major histocompatibility complex (MHC) presentation [26,27]. CAR-T-cell therapy has produced substantial clinical responses in several hematologic malignancies, establishing a strong rationale for its exploration in solid tumors [28–31]. However, the translation of CAR-T-cell therapy into solid tumors has been constrained by antigen heterogeneity, inadequate T-cell trafficking and infiltration, physical stromal barriers, and immunosuppressive signals within the tumor microenvironment (TME) [32–35].

Several recent reviews have summarized CAR-T-cell therapy for HCC from broad translational and mechanistic perspectives [36,37]. Compared with these reviews, this article aims to review recent advances in CAR-T-cell therapy for hepatocellular carcinoma.

CAR-T Immunotherapy

CAR-T-cell therapy uses genetically modified T lymphocytes to recognize tumor-associated antigens and mediate tumor cell killing [26,27]. Peripheral blood mononuclear cells (PBMCs) are commonly obtained through leukapheresis, followed by T-cell enrichment, activation, genetic transduction or transfection, ex vivo expansion, quality control, and reinfusion into the patient [26,27,38,39]. The single-chain variable fragment (scFv) within the extracellular domain mediates antigen recognition, whereas intracellular signaling domains activate T-cell cytotoxicity, proliferation, and cytokine release [27,40,41]. Figure 1 illustrates the generation process, target recognition, and antitumor mechanisms of chimeric antigen receptor T-cell therapy in hepatocellular carcinoma (Figure 1).

Figure 1.

Figure 1

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Generation process, target recognition, and antitumor mechanisms of chimeric antigen receptor T-cell therapy in hepatocellular carcinoma. Peripheral blood mononuclear cells (PBMCs) are collected from patients through leukapheresis. T lymphocytes are isolated, activated, genetically engineered to express chimeric antigen receptors (CARs), expanded ex vivo, and reinfused into patients after quality control. After infusion, CAR-T cells migrate to tumor sites and recognize hepatocellular carcinoma (HCC)-associated target antigens, including carcinoembryonic antigen (CEA), glypican-3 (GPC3), alpha-fetoprotein (AFP), epidermal growth factor receptor variant III (EGFRvIII), B7 homolog 3 (B7H3), mucin 1 (MUC1), natural killer group 2 member D ligand (NKG2DL), programmed death-ligand 1 (PD-L1), CD133, CD147, CD44, death receptor 5 (DR5), MG7, human epidermal growth factor receptor 2 (HER2), transforming growth factor beta (TGF-beta), and epithelial cell adhesion molecule (EpCAM). After antigen recognition through the single-chain variable fragment (scFv) domain, CAR-T cells become activated and induce tumor cell lysis through cytotoxic molecules and inflammatory cytokines. The figure was originally created by the authors using Adobe Illustrator and professional graphic design software and was not reproduced or adapted from previously published sources.

Unlike conventional T-cell receptor (TCR)-mediated recognition, CAR-mediated antigen recognition does not require peptide presentation by MHC molecules [27]. This feature allows CAR-T cells to recognize surface antigens on tumor cells even when tumors downregulate MHC expression as an immune-evasion mechanism [27,42]. Nevertheless, the efficacy of CAR-T-cell therapy in solid tumors depends on target antigen specificity, antigen density, T-cell persistence, and the suppressive characteristics of the TME [32–35].

Structural Design and Evolution of CAR-T Cells

A CAR molecule generally contains an extracellular antigen-binding domain, a hinge or spacer region, a transmembrane domain, and intracellular signaling modules [40,41]. The extracellular antigen-binding domain is most commonly derived from an antibody scFv and determines target specificity [27,40]. The hinge and transmembrane domains affect receptor flexibility, stability, antigen accessibility, and cell-surface expression [40].

First-generation CARs contained CD3ζ or Fc receptor gamma chain signaling domains but lacked costimulatory domains, resulting in limited in vivo persistence and antitumor activity [41,43,44]. Second-generation CARs incorporated one costimulatory domain, such as CD28 or 4-1BB, thereby improving T-cell expansion, persistence, and cytotoxic function [44,45]. Third-generation CARs contain 2 or more costimulatory domains, such as CD28 combined with 4-1BB or OX40, to further enhance activation and survival signals [41,45,46].

Fourth-generation CAR-T cells, also known as T cells redirected for universal cytokine-mediated killing (TRUCKs), are engineered to secrete cytokines or immune-modulating molecules after antigen recognition [45,47]. Fifth-generation CAR-T-cell designs incorporate additional intracellular signaling modules or gene-editing strategies to improve safety, reduce rejection, and enhance antitumor activity [41,48]. These structural innovations provide the basis for optimizing CAR-T-cell therapy in HCC and other solid tumors [32,48,49]. Figure 2 depicts the structural evolution of chimeric antigen receptor (CAR) T-cell constructs from the first to the fifth generation (Figure 2).

Figure 2.

Figure 2

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Structural evolution of chimeric antigen receptor T-cell constructs from first- to fifth-generation CARs. The first-generation chimeric antigen receptor (CAR) contains an extracellular antigen-binding domain, a transmembrane domain, and an intracellular CD3ζ signaling domain without costimulatory signaling. Second-generation CARs incorporate one costimulatory domain, such as CD28 or 4-1BB, to enhance T-cell activation and persistence. Third-generation CARs contain 2 or more tandem costimulatory domains to further improve antitumor activity. Fourth-generation CAR-T cells, also termed T cells redirected for universal cytokine-mediated killing (TRUCKs), are engineered to secrete cytokines following activation to modulate the tumor microenvironment (TME). Fifth-generation CAR-T cells incorporate additional intracellular signaling modifications and gene-editing strategies to improve antitumor efficacy and reduce immune rejection. The figure was originally created by the authors using Adobe Illustrator and professional graphic design software and was not reproduced or adapted from previously published sources.

CAR-T-cell therapy has achieved clear clinical success in hematologic malignancies, with studies reporting high remission rates in refractory B-cell malignancies [28–31]. In contrast, the development of CAR-T-cell therapy for solid tumors has been more difficult because tumor-associated antigens are often heterogeneously expressed and may also be present at low levels in normal tissues [32,42,50].

Successful CAR-T-cell therapy for solid tumors requires identification of targets that are highly expressed in tumor cells but limited in essential normal tissues [33,42,50]. Additional barriers include inadequate homing of CAR-T cells to tumor sites, limited penetration into dense tumor tissue, metabolic stress, checkpoint-mediated exhaustion, and suppression by regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and cytokines such as transforming growth factor beta (TGF-beta) [32–35].

Several strategies have been investigated to improve CAR-T-cell activity in solid tumors, including regional infusion, dual-target CAR design, armored CAR-T cells, checkpoint blockade combinations, cytokine engineering, and modification of the TME [32–35,49]. These approaches are particularly relevant to HCC, which develops in a tolerogenic liver environment and frequently coexists with chronic inflammation and cirrhosis [4,7,8].

CAR-T Therapy for Hepatocellular Carcinoma

HCC is characterized by molecular heterogeneity, vascular invasion, high recurrence risk, and an immunologically complex microenvironment [4,7,8,20]. Immune checkpoint inhibitors and antiangiogenic combinations have changed the systemic treatment landscape for advanced HCC, but resistance and limited durable responses remain major challenges [15,16,20,23–25]. CAR-T-cell therapy provides a target-directed approach that may complement existing systemic and locoregional therapies [27,32,42,50].

According to registered clinical studies and published reports, multiple CAR-T-cell strategies for HCC have focused on antigens such as GPC3, CEA, CD133, AFP, EGFRvIII, B7H3, MUC1, NKG2DL, PD-L1/c-Met, CD147, CD44, DR5, MG7, human epidermal growth factor receptor 2 (HER2), TGF-beta, and EpCAM [49,51–88]. The current evidence remains dominated by early-phase trials and preclinical studies, and large randomized trials are still lacking [54,55,61,64,80].

HCC-Associated CAR-T Targets

CEA

Carcinoembryonic antigen (CEA), also known as CEACAM5, is a tumor-associated antigen expressed in several epithelial malignancies [51]. Anti-CEA CAR-T-cell approaches have been explored using hepatic artery infusion to enhance regional delivery to liver lesions [52]. In a phase Ib study of intraarterial CAR-T-cell therapy combined with selective internal radiation therapy for CEA-positive liver metastases, the approach was feasible and did not produce severe cytokine release syndrome or neurotoxicity [52].

GPC3

Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan that is overexpressed in many HCC tissues and is associated with tumor progression [53]. GPC3 is one of the most widely investigated targets for CAR-T-cell therapy in HCC [54,55,89,90]. In early-phase clinical studies, GPC3-targeted CAR-T cells demonstrated acceptable safety and preliminary antitumor activity in selected patients with advanced GPC3-positive HCC [54]. Fourth-generation GPC3-targeted CAR-T-cell strategies secreting interleukin 7 (IL-7) and C-C motif chemokine ligand 19 (CCL19) have also been explored to enhance immune cell recruitment and antitumor activity [55].

CD133

CD133 is a transmembrane glycoprotein expressed in cancer stem-like cells and has been associated with aggressive tumor biology and poor prognosis in HCC [56–60]. CD133-directed CAR-T-cell therapy has been evaluated in patients with advanced malignancies and HCC [61,64]. In a single-arm phase II trial of CD133-directed CAR-T cells in advanced HCC, partial response and stable disease were observed in a subset of patients, with median overall survival and progression-free survival suggesting preliminary clinical activity [64].

AFP

Alpha-fetoprotein (AFP) is a classical biomarker of HCC and has been investigated as a target for T-cell-based immunotherapy [65]. Because AFP is an intracellular and secreted antigen, AFP-targeted CAR-T-cell strategies rely on recognition of AFP-derived peptide-major histocompatibility complex complexes rather than direct surface antigen binding [65]. Preclinical findings support the feasibility of AFP-MHC complex targeting, although further clinical evidence is needed [65].

EGFRvIII

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutant form of epidermal growth factor receptor that has been detected in several malignancies, including HCC [66–68]. EGFRvIII-specific CAR-T cells produced using the piggyBac transposon system inhibited HCC cell growth in vitro and in vivo, supporting EGFRvIII as a potential HCC CAR-T target [69].

B7H3

B7 homolog 3 (B7H3) is a member of the B7 immunoglobulin superfamily and is overexpressed in several solid tumors [70]. Tandem CAR-T cells targeting CD70 and B7H3 showed potent preclinical activity against multiple solid tumors, suggesting a potential strategy for tumors with heterogeneous antigen expression [70]. Clinical translation of B7H3-targeted CAR-T cells in HCC remains under investigation.

MUC1 and NKG2DL

Mucin 1 (MUC1) is a transmembrane glycoprotein involved in tumor progression and immune regulation [71,72]. MUC1 expression has been observed in HCC models, and MUC1-targeted CAR-T-cell approaches have shown antitumor activity in experimental HCC systems [73]. Natural killer group 2 member D ligand (NKG2DL) is another target of interest because NKG2D ligands are frequently induced by cellular stress and malignant transformation [74,75]. NKG2D-based CAR-T cells have eradicated NKG2DL-positive HCC cells in preclinical models [77].

PD-L1/c-Met, CD147, CD44, and Other Targets

Programmed death-ligand 1 (PD-L1) contributes to immune evasion by interacting with programmed death 1 (PD-1) on T cells [78]. Dual-targeting strategies involving PD-L1 and c-Met have been explored as a way to combine tumor targeting with checkpoint-related mechanisms [79]. CD147 is highly expressed in HCC and is associated with invasion, metastasis, and poor prognosis [80–82]. Anti-CD147 CAR-T cells demonstrated antitumor efficacy against HCC in preclinical studies, and inducible CD147-targeted CAR-T designs have been developed to improve controllability [80,86]. CD44 is a cancer stem cell-associated marker, and CD44-targeted CAR-T cells suppressed HCC growth in experimental models [87,88]. Additional targets, including death receptor 5 (DR5), MG7, HER2, TGF-beta, and EpCAM, are being explored in registered studies and preclinical reports [49].

Clinical Studies of CAR-T Therapy in HCC

Most clinical studies of CAR-T-cell therapy for HCC are early-phase trials designed to evaluate safety, feasibility, dose escalation, route of administration, and preliminary efficacy [36,54,55,61,64,91]. GPC3 remains the most clinically advanced HCC-related CAR-T target, with published phase I data supporting tolerability and early signs of activity [54,55]. CD133-directed CAR-T-cell therapy has also been evaluated in advanced HCC, with disease stabilization observed in some patients [61,64].

Regional delivery strategies, including hepatic artery infusion, transcatheter arterial infusion, and intratumoral injection, have been used in several trials to increase local exposure and reduce systemic toxicity [51,64]. However, the available clinical evidence remains limited by small sample sizes, heterogeneous trial designs, variable target expression, and incomplete reporting of long-term outcomes [54,55,61,64]. Table 1 summarizes registered clinical studies of CAR-T-cell therapy targeting HCC-related antigens.

Table 1.

Relevant clinical studies.

Target Intervention and reference Phase Main findings Status NCT number CAR design First posted Route
CEA Anti-CEA CAR-T cells [52] Phase 1 No results posted Completed NCT01373047 2nd generation 2011 Hepatic artery infusion
CEA Anti-CEA CAR-T cells [52] Phase 1 No results posted Recruiting NCT05240950 Unknown 2022 Intravenous infusion
CEA CEA CAR-T cells [52] Phase 1/2 No results posted Recruiting NCT04348643 Unknown 2020 Intravenous injection
CEA Anti-CEA CAR-T cells plus SIR-Spheres [52] Phase 1 No results posted Completed NCT02416466 Unknown 2015 Hepatic artery infusion
CEA Anti-CEA CAR-T cells [52] Phase 1 CEA and CA19-9 levels normalized for 2–3 months Completed NCT02850536 CD28/CD3ζ 2016 Hepatic artery infusion
GPC3 Y035 [54] Phase 1 3-year, 1-year, and 6-month OS rates were 10.5%, 42.0%, and 50.3% Completed NCT02395250 Humanized anti-GPC3 CAR 2015 Intravenous injection
GPC3 CT011 [54] Not applicable Tumor progression-free survival > 36 months Active, not recruiting NCT03302403 Unknown 2017 Intravenous injection
GPC3 4G-CAR-GPC3 T cells [54] Phase 1 ORR 16.7%; DCR 50%; median PFS 4.2 months Completed NCT03980288 4th generation 2019 Intravenous injection
GPC3 CAR(hYP7)-T [54] Phase 1 No results posted Recruiting NCT05003895 Unknown 2021 Injection
GPC3 Anti-GPC3 CAR-T cells [54] Early Phase 1 No results posted Recruiting NCT04951141 Unknown 2021 Intratumoral injection
GPC3 TC-CAR031 [54] Phase 1 No results posted Recruiting NCT05155189 Unknown 2021 Intravenous infusion
GPC3 GPC3-CAR-T cells [54] Phase 1 No results posted Suspended NCT04506983 Unknown 2020 Intravenous infusion
GPC3 Anti-GPC3 CAR-T [54] Phase 1/2 No results posted Unknown NCT03084380 2nd generation, 4-1BB/CD3ζ 2017 Intravenous or catheter injection
GPC3 Ori-C101 [54] Phase 1/2 No results posted Recruiting NCT05652920 Unknown 2022 Hepatic arterial infusion
GPC3/TGF-beta GPC3 and/or TGF-beta targeting CAR-T cells [49,55] Phase 1 Tumors were completely eliminated within one month in one patient Recruiting NCT03198546 3rd/4th generation 2017 Systemic or local infusion
CD133 CART-133 [61,64] Phase 1/2 ORR 7%; SD 64%; median OS 12 months; median PFS 6.8 months Completed NCT02541370 CD137/CD3ζ 2015 Injection
AFP ET1402L1-CAR-T cells [65] Phase 1 No results posted Terminated NCT03349255 CD28/CD3ζ 2017 Intrahepatic artery catheter or intravenous infusion
EGFRvIII/DR5/NY-ESO-1 CAR-T cells [49,69] Phase 1/2 No results posted Unknown NCT03941626 Unknown 2019 Injection
B7H3 fhB7H3.CAR-Ts [70] Phase 1/2 No results posted Recruiting NCT05323201 Unknown 2022 Transhepatic arterial infusion
MUC1 Anti-MUC1 CAR-T cells [73] Phase 1/2 No results posted Unknown NCT02587689 Unknown 2015 Injection
MUC1/HER2/GPC3/EGFR/B7H3 CAR-TILs [49,73] Phase 1 No results posted Unknown NCT04842812 Unknown 2021 Injection
NKG2D KD-025 CAR-T cells [77] Phase 1 No results posted Unknown NCT04550663 Unknown 2020 Injection
NKG2D NKR-2 cells [77] Phase 1 No results posted Unknown NCT03370198 Unknown 2017 Hepatic transarterial administration
NKG2D NKR-2 cells [77] Phase 1 No results posted Unknown NCT03310008 Unknown 2017 Injection
NKG2D NKG2D CAR-T cells [77] Early Phase 1 No results posted Recruiting NCT05248048 Unknown 2022 Hepatic artery transfusion
PD-L1/c-Met c-Met/PD-L1 CAR-T cells [79] Early Phase 1 No results posted Unknown NCT03672305 Unknown 2018 Intravenous drip
PD-L1 HerinCAR-PD1 cells [49] Phase 1/2 No results posted Unknown NCT02862028 Unknown 2016 Intratumoral injection
CD147 CD147-CAR-T [80,86] Phase 1 No results posted Unknown NCT03993743 Unknown 2019 Hepatic artery infusion
MG7 MG7-CAR-T cells [49] Phase 1/2 No results posted Unknown NCT02862704 2nd generation, 4-1BB/CD3ζ 2016 Intratumoral injection
EpCAM EpCAM-targeted CAR-T cells [49] Phase 1/2 No results posted Unknown NCT03013712 2nd generation, CD28/CD3ζ 2017 Vascular interventional or endoscopic administration
EpCAM EpCAM-targeted CAR-T cells [49] Not applicable No results posted Unknown NCT02729493 Unknown 2016 Injection
IM83 IM83 CAR-T cells [49] Phase 1 No results posted Recruiting NCT05123209 Unknown 2021 Injection
OX40 CpG-ODN [49] Phase 1 No results posted Recruiting NCT04952272 Unknown 2021 Intratumoral injection
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Abbreviations: AFP, alpha-fetoprotein; B7H3, B7 homolog 3; CAR, chimeric antigen receptor; CEA, carcinoembryonic antigen; DCR, disease control rate; DR5, death receptor 5; EGFRvIII, epidermal growth factor receptor variant III; EpCAM, epithelial cell adhesion molecule; GPC3, glypican-3; HCC, hepatocellular carcinoma; HER2, human epidermal growth factor receptor 2; MUC1, mucin 1; NKG2D, natural killer group 2 member D; NY-ESO-1, New York esophageal squamous cell carcinoma 1; ORR, overall response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; SD, stable disease; TGF-beta, transforming growth factor beta. Table note: References in square brackets indicate sources cited in the main reference list. The NCT number is retained as the clinical trial registration identifier. Trial information was summarized from registered clinical studies and the corresponding cited literature, with the final search conducted on March 27, 2023.

Safety, Toxicity, and Barriers to Clinical Translation

CAR-T-cell therapy can be associated with cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome, cytopenias, and on-target/off-tumor toxicity [92,93]. In solid tumors, safety concerns are amplified when target antigens are also expressed in normal tissues [32,42,50]. Careful target selection and controllable CAR designs are therefore important for improving the therapeutic index in HCC [80,86].

The TME is a major barrier to CAR-T-cell efficacy in HCC [32–35]. Physical barriers, hypoxia, metabolic stress, immune checkpoint signaling, TGF-beta-mediated suppression, regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages can impair CAR-T-cell trafficking, activation, and persistence [32–35,94]. Antigen heterogeneity and antigen loss can further reduce response durability [49].

Potential solutions include dual- or multi-target CAR constructs, cytokine-armored CAR-T cells, checkpoint-resistant CAR-T cells, hypoxia-responsive designs, regional infusion, and combination therapy with immune checkpoint inhibitors, antiangiogenic agents, targeted therapies, or locoregional treatments [32–35,49,55,89,90,94].

Future Directions

Future development of CAR-T-cell therapy for HCC should prioritize accurate target selection, standardized antigen-expression assessment, and rational trial design. Biomarker-driven enrollment may help identify patients most likely to benefit from target-specific CAR-T-cell therapy [53,54,64,80]. Multi-antigen strategies may reduce antigen escape, whereas inducible or switchable CAR systems may improve safety and controllability [49,80,86].

Combination strategies are also likely to be important. CAR-T-cell therapy may be combined with immune checkpoint inhibitors to counteract T-cell exhaustion, with antiangiogenic agents to improve tumor perfusion and immune infiltration, or with locoregional therapies to enhance antigen release and local immune activation [20,23–25,32–35]. Regional delivery may further improve the balance between efficacy and toxicity in liver tumors [52,64].

Long-term clinical translation will require larger multicenter trials, harmonized toxicity reporting, standardized response assessment, and extended follow-up for delayed adverse events and durability of response [54,55,64,93]. Manufacturing optimization and cost reduction will also be essential for broader clinical application.

Conclusions

CAR-T-cell therapy is an emerging immunotherapeutic strategy for HCC. Recent advances in CAR design, target identification, and early clinical translation have expanded the therapeutic potential of CAR-T cells in this disease. GPC3, CD133, AFP, EGFRvIII, NKG2DL, CD147, and EpCAM are among the most actively investigated HCC-related targets. However, tumor heterogeneity, antigen escape, limited tumor infiltration, and the immunosuppressive TME remain major barriers. Future research should focus on safer CAR engineering, multi-target strategies, rational combination therapies, and well-designed clinical trials to clarify the clinical role of CAR-T-cell therapy in HCC1.

Footnotes

Financial support: This work was supported by grants from the general project of the Development Fund of the Affiliated Hospital of Xuzhou Medical University (XYFM2021032), Linyi Key R&D Program (2022YX0028)

Conflict of interest: None declared

Publisher’s note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher

Declaration of Figures’ Authenticity: All figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.

Data Availability

All data supporting the findings of this review are available within the manuscript and its cited sources.

References

  • 1.Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. Cancer J Clin. 2022;72(1):7–33. doi: 10.3322/caac.21708. [DOI] [PubMed] [Google Scholar]
  • 2.Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. Cancer J Clin. 2023;73(1):17–48. doi: 10.3322/caac.21763. [DOI] [PubMed] [Google Scholar]
  • 3.Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2021;71(3):209–49. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
  • 4.Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. doi: 10.1038/s41572-020-00240-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Petrick JL, Florio AA, Znaor A, et al. International trends in hepatocellular carcinoma incidence, 1978–2012. Int J Cancer. 2020;147(2):317–30. doi: 10.1002/ijc.32723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492. [DOI] [PubMed] [Google Scholar]
  • 7.Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156(2):477–91e1. doi: 10.1053/j.gastro.2018.08.065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Yang JD, Hainaut P, Gores GJ, et al. A global view of hepatocellular carcinoma: Trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589–604. doi: 10.1038/s41575-019-0186-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Sugawara Y, Hibi T. Surgical treatment of hepatocellular carcinoma. Biosci Trends. 2021;15(3):138–41. doi: 10.5582/bst.2021.01094. [DOI] [PubMed] [Google Scholar]
  • 10.Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–14. doi: 10.1016/S0140-6736(18)30010-2. [DOI] [PubMed] [Google Scholar]
  • 11.Pinna AD, Yang T, Mazzaferro V, et al. Liver transplantation and hepatic resection can achieve cure for hepatocellular carcinoma. Ann Surg. 2018;268(5):868–75. doi: 10.1097/SLA.0000000000002889. [DOI] [PubMed] [Google Scholar]
  • 12.Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907–17. doi: 10.1016/S0140-6736(03)14964-1. [DOI] [PubMed] [Google Scholar]
  • 13.Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90. doi: 10.1056/NEJMoa0708857. [DOI] [PubMed] [Google Scholar]
  • 14.Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66. doi: 10.1016/S0140-6736(16)32453-9. [DOI] [PubMed] [Google Scholar]
  • 15.Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–52. doi: 10.1016/S1470-2045(18)30351-6. [DOI] [PubMed] [Google Scholar]
  • 16.El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502. doi: 10.1016/S0140-6736(17)31046-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–73. doi: 10.1016/S0140-6736(18)30207-1. [DOI] [PubMed] [Google Scholar]
  • 18.Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63. doi: 10.1056/NEJMoa1717002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–96. doi: 10.1016/S1470-2045(18)30937-9. [DOI] [PubMed] [Google Scholar]
  • 20.Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018;15(10):599–616. doi: 10.1038/s41571-018-0073-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Zhang DZ, Niu JQ. [Clinical advances in targeted therapy and immunotherapy for hepatocellular carcinoma]. Zhonghua Gan Zang Bing Za Zhi. 2019;27(11):834–37. doi: 10.3760/cma.j.issn.1007-3418.2019.11.005. [in Chinese] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Galon J, Bruni D. Tumor immunology and tumor evolution: Intertwined histories. Immunity. 2020;52(1):55–81. doi: 10.1016/j.immuni.2019.12.018. [DOI] [PubMed] [Google Scholar]
  • 23.Liu Z, Lin Y, Zhang J, et al. Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):447. doi: 10.1186/s13046-019-1412-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Faivre S, Rimassa L, Finn RS. Molecular therapies for HCC: Looking outside the box. J Hepatol. 2020;72(2):342–52. doi: 10.1016/j.jhep.2019.09.010. [DOI] [PubMed] [Google Scholar]
  • 25.Sonbol MB, Riaz IB, Naqvi SAA, et al. Systemic therapy and sequencing options in advanced hepatocellular carcinoma: A systematic review and network meta-analysis. JAMA Oncol. 2020;6(12):e204930. doi: 10.1001/jamaoncol.2020.4930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Jogalekar MP, Rajendran RL, Khan F, et al. CAR T-Cell-Based gene therapy for cancers: New perspectives, challenges, and clinical developments. Front Immunol. 2022;13:925985. doi: 10.3389/fimmu.2022.925985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.June CH, O’Connor RS, Kawalekar OU, et al. CAR T cell immunotherapy for human cancer. Science. 2018;359(6382):1361–65. doi: 10.1126/science.aar6711. [DOI] [PubMed] [Google Scholar]
  • 28.Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38. doi: 10.1126/scitranslmed.3005930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–49. doi: 10.1200/JCO.2014.56.2025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. Lancet. 2015;385(9967):517–28. doi: 10.1016/S0140-6736(14)61403-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129(25):3322–31. doi: 10.1182/blood-2017-02-769208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Lindo L, Wilkinson LH, Hay KA. Befriending the hostile tumor microenvironment in CAR T-cell therapy. Front Immunol. 2020;11:618387. doi: 10.3389/fimmu.2020.618387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Cadilha BL, Benmebarek MR, Dorman K, et al. Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors. Sci Adv. 2021;7(24):5781. doi: 10.1126/sciadv.abi5781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Füchsl F, Krackhardt AM. Paving the way to solid tumors: challenges and strategies for adoptively transferred transgenic T cells in the tumor microenvironment. Cancers (Basel) 2022;14(17):4192. doi: 10.3390/cancers14174192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Newick K, O’Brien S, Moon E, Albelda SM. CAR T cell therapy for solid tumors. Annu Rev Med. 2017;68:139–52. doi: 10.1146/annurev-med-062315-120245. [DOI] [PubMed] [Google Scholar]
  • 36.Zhou Y, Wei S, Xu M, et al. CAR-T cell therapy for hepatocellular carcinoma: current trends and challenges. Front Immunol. 2024;15:1489649. doi: 10.3389/fimmu.2024.1489649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Elahi R, Alami Idrissi Y, Saeed A. CAR-T cell therapy in hepatocellular carcinoma: from mechanistic insights to clinical translation. Cancer Treat Rev. 2025;141:103046. doi: 10.1016/j.ctrv.2025.103046. [DOI] [PubMed] [Google Scholar]
  • 38.Teoh PJ, Chng WJ. CAR T-cell therapy in multiple myeloma: more room for improvement. Blood Cancer J. 2021;11(4):84. doi: 10.1038/s41408-021-00469-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Marofi F, Rahman HS, Achmad MH, et al. A deep insight into CAR-T cell therapy in non-hodgkin lymphoma: Application, opportunities, and future directions. Front Immunol. 2021;12:681984. doi: 10.3389/fimmu.2021.681984. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 40.Hudecek M, Sommermeyer D, Kosasih PL, et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol Res. 2015;3(2):125–35. doi: 10.1158/2326-6066.CIR-14-0127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Elahi R, Khosh E, Tahmasebi S, Esmaeilzadeh A. Immune cell hacking: challenges and clinical approaches to create smarter generations of chimeric antigen receptor T cells. Front Immunol. 2018;9:1717. doi: 10.3389/fimmu.2018.01717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Ma S, Li X, Wang X, et al. Current progress in CAR-T cell therapy for solid tumors. Int J Biol Sci. 2019;15(12):2548–60. doi: 10.7150/ijbs.34213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Hyllner J, Mason C, Wilmut I. Cells: from Robert Hooke to cell therapy – A 350 year journey. Philos Trans R Soc Lond B Biol Sci. 2015;370(1680):20150320. doi: 10.1098/rstb.2015.0320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121(5):1822–26. doi: 10.1172/JCI46110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Huang R, Li X, He Y, et al. Recent advances in CAR-T cell engineering. J Hematol Oncol. 2020;13(1):86. doi: 10.1186/s13045-020-00910-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Au R. Immunooncology: Can the right chimeric antigen receptors T-cell design be made to cure all types of cancers and will it be covered? J Pharm (Cairo) 2017;2017:7513687. doi: 10.1155/2017/7513687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Duan D, Wang K, Wei C, et al. The BCMA-targeted fourth-generation CAR-T cells secreting IL-7 and CCL19 for therapy of refractory/recurrent multiple myeloma. Front Immunol. 2021;12:609421. doi: 10.3389/fimmu.2021.609421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Roselli E, Faramand R, Davila ML. Insight into next-generation CAR therapeutics: Designing CAR T cells to improve clinical outcomes. J Clin Invest. 2021;131(2):e142030. doi: 10.1172/JCI142030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Qu C, Zhang H, Cao H, et al. Tumor buster – where will the CAR-T cell therapy ‘missile’ go? Mol Cancer. 2022;21(1):201. doi: 10.1186/s12943-022-01669-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Guo F, Cui J. CAR-T in solid tumors: Blazing a new trail through the brambles. Life Sci. 2020;260:118300. doi: 10.1016/j.lfs.2020.118300. [DOI] [PubMed] [Google Scholar]
  • 51.Han ZW, Lyv ZW, Cui B, et al. The old CEACAMs find their new role in tumor immunotherapy. Invest New Drugs. 2020;38(6):1888–98. doi: 10.1007/s10637-020-00955-w. [DOI] [PubMed] [Google Scholar]
  • 52.Katz SC, Hardaway J, Prince E, et al. HITM-SIR: Phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA(+) liver metastases. Cancer Gene Ther. 2020;27(5):341–55. doi: 10.1038/s41417-019-0104-z. [DOI] [PubMed] [Google Scholar]
  • 53.Kaseb AO, Hassan M, Lacin S, et al. Evaluating clinical and prognostic implications of Glypican-3 in hepatocellular carcinoma. Oncotarget. 2016;7(43):69916–26. doi: 10.18632/oncotarget.12066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Shi D, Shi Y, Kaseb AO, et al. Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma: results of phase I trials. Clin Cancer Res. 2020;26(15):3979–89. doi: 10.1158/1078-0432.CCR-19-3259. [DOI] [PubMed] [Google Scholar]
  • 55.Pang N, Shi J, Qin L, et al. IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J Hematol Oncol. 2021;14(1):118. doi: 10.1186/s13045-021-01128-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Glumac PM, LeBeau AM. The role of CD133 in cancer: A concise review. Clin Transl Med. 2018;7(1):18. doi: 10.1186/s40169-018-0198-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Schmohl JU, Vallera DA. CD133, selectively targeting the root of cancer. Toxins (Basel) 2016;8(6):165. doi: 10.3390/toxins8060165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Won C, Kim BH, Yi EH, et al. Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma. Hepatology. 2015;62(4):1160–73. doi: 10.1002/hep.27968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Kohga K, Tatsumi T, Takehara T, et al. Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma. J Hepatol. 2010;52(6):872–79. doi: 10.1016/j.jhep.2009.12.030. [DOI] [PubMed] [Google Scholar]
  • 60.Yang XR, Xu Y, Yu B, et al. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut. 2010;59(7):953–62. doi: 10.1136/gut.2008.176271. [DOI] [PubMed] [Google Scholar]
  • 61.Wang Y, Chen M, Wu Z, et al. CD133-directed CAR T cells for advanced metastasis malignancies: A phase I trial. Oncoimmunology. 2018;7(7):e1440169. doi: 10.1080/2162402X.2018.1440169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Ho JW, Pang RW, Lau C, et al. Significance of circulating endothelial progenitor cells in hepatocellular carcinoma. Hepatology. 2006;44(4):836–43. doi: 10.1002/hep.21353. [DOI] [PubMed] [Google Scholar]
  • 63.Gao D, Nolan DJ, Mellick AS, Bambino K, et al. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science. 2008;319(5860):195–98. doi: 10.1126/science.1150224. [DOI] [PubMed] [Google Scholar]
  • 64.Dai H, Tong C, Shi D, et al. Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: A single-arm, open-label, phase II trial. Oncoimmunology. 2020;9(1):1846926. doi: 10.1080/2162402X.2020.1846926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Liu H, Xu Y, Xiang J, et al. Targeting alpha-fetoprotein (AFP)-MHC complex with CAR T-cell therapy for liver cancer. Clin Cancer Res. 2017;23(2):478–88. doi: 10.1158/1078-0432.CCR-16-1203. [DOI] [PubMed] [Google Scholar]
  • 66.Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): Where wild things are altered. FEBS J. 2013;280(21):5350–70. doi: 10.1111/febs.12393. [DOI] [PubMed] [Google Scholar]
  • 67.Luo X, Xie H, Long X, et al. EGFRvIII mediates hepatocellular carcinoma cell invasion by promoting S100 calcium binding protein A11 expression. PLoS One. 2013;8(12):e83332. doi: 10.1371/journal.pone.0083332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Xu W, Song F, Wang B, et al. The effect of and mechanism underlying autophagy in hepatocellular carcinoma induced by CH12, a monoclonal antibody directed against epidermal growth factor receptor variant III. Cell Physiol Biochem. 2018;46(1):226–37. doi: 10.1159/000488425. [DOI] [PubMed] [Google Scholar]
  • 69.Ma Y, Chen Y, Yan L, et al. EGFRvIII-specific CAR-T cells produced by piggyBac transposon exhibit efficient growth suppression against hepatocellular carcinoma. Int J Med Sci. 2020;17(10):1406–14. doi: 10.7150/ijms.45603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Yang M, Tang X, Zhang Z, et al. Tandem CAR-T cells targeting CD70 and B7-H3 exhibit potent preclinical activity against multiple solid tumors. Theranostics. 2020;10(17):7622–34. doi: 10.7150/thno.43991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Nath S, Mukherjee P. MUC1: A multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med. 2014;20(6):332–42. doi: 10.1016/j.molmed.2014.02.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Chen W, Zhang Z, Zhang S, et al. MUC1: Structure, function, and clinic application in epithelial cancers. Int J Mol Sci. 2021;22(12):6567. doi: 10.3390/ijms22126567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Jiang Z, Cheng L, Wu Z, et al. Transforming primary human hepatocytes into hepatocellular carcinoma with genetically defined factors. EMBO Rep. 2022;23(6):e54275. doi: 10.15252/embr.202154275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Zhang J, Basher F, Wu JD. NKG2D ligands in tumor immunity: Two sides of a coin. Front Immunol. 2015;6:97. doi: 10.3389/fimmu.2015.00097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Dhar P, Wu JD. NKG2D and its ligands in cancer. Curr Opin Immunol. 2018;51:55–61. doi: 10.1016/j.coi.2018.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Kamimura H, Yamagiwa S, Tsuchiya A, et al. Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence. J Hepatol. 2012;56(2):381–88. doi: 10.1016/j.jhep.2011.06.017. [DOI] [PubMed] [Google Scholar]
  • 77.Sun B, Yang D, Dai H, et al. Eradication of hepatocellular carcinoma by NKG2D-based CAR-T cells. Cancer Immunol Res. 2019;7(11):1813–23. doi: 10.1158/2326-6066.CIR-19-0026. [DOI] [PubMed] [Google Scholar]
  • 78.Cha JH, Chan LC, Li CW, et al. Mechanisms controlling PD-L1 expression in cancer. Mol Cell. 2019;76(3):359–70. doi: 10.1016/j.molcel.2019.09.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Xiong C, Mao Y, Wu T, et al. Optimized expression and characterization of a novel fully human bispecific single-chain diabody targeting vascular endothelial growth factor165 and programmed death-1 in pichia pastoris and evaluation of antitumor activity in vivo. Int J Mol Sci. 2018;19(10):2900. doi: 10.3390/ijms19102900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Tseng HC, Xiong W, Badeti S, et al. Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma. Nat Commun. 2020;11(1):4810. doi: 10.1038/s41467-020-18444-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Li Y, Xu J, Chen L, et al. HAb18G (CD147), a cancer-associated biomarker and its role in cancer detection. Histopathology. 2009;54(6):677–87. doi: 10.1111/j.1365-2559.2009.03280.x. [DOI] [PubMed] [Google Scholar]
  • 82.Lu M, Wu J, Hao ZW, et al. Basolateral CD147 induces hepatocyte polarity loss by E-cadherin ubiquitination and degradation in hepatocellular carcinoma progress. Hepatology. 2018;68(1):317–32. doi: 10.1002/hep.29798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Bian H, Zheng JS, Nan G, et al. Randomized trial of [131I] metuximab in treatment of hepatocellular carcinoma after percutaneous radiofrequency ablation. J Natl Cancer Inst. 2014;106(9):dju239. doi: 10.1093/jnci/dju239. [DOI] [PubMed] [Google Scholar]
  • 84.Chen H, Nan G, Wei D, et al. Hepatic artery injection of (131)I-metuximab combined with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: A prospective nonrandomized, multicenter clinical trial. J Nucl Med. 2022;63(4):556–59. doi: 10.2967/jnumed.121.262136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Xu J, Shen ZY, Chen XG, et al. A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation. Hepatology. 2007;45(2):269–76. doi: 10.1002/hep.21465. [DOI] [PubMed] [Google Scholar]
  • 86.Zhang RY, Wei D, Liu ZK, et al. doxycycline inducible chimeric antigen receptor T cells targeting CD147 for hepatocellular carcinoma therapy. Front Cell Dev Biol. 2019;7:233. doi: 10.3389/fcell.2019.00233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Chen C, Zhao S, Karnad A, Freeman JW. The biology and role of CD44 in cancer progression: Therapeutic implications. J Hematol Oncol. 2018;11(1):64. doi: 10.1186/s13045-018-0605-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Wang H, Ye X, Ju Y, et al. Minicircle DNA-mediated CAR T cells targeting CD44 suppressed hepatocellular carcinoma both in vitro and in vivo. Onco Targets Ther. 2020;13:3703–16. doi: 10.2147/OTT.S247836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Makkouk A, Yang XC, Barca T, et al. Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma. J Immunother Cancer. 2021;9(12):e003441. doi: 10.1136/jitc-2021-003441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Li D, Li N, Zhang YF, et al. Persistent polyfunctional chimeric antigen receptor T cells that target glypican 3 eliminate orthotopic hepatocellular carcinomas in Mice. Gastroenterology. 2020;158(8):2250–65e20. doi: 10.1053/j.gastro.2020.02.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Wei J, Guo Y, Wang Y, et al. Clinical development of CAR T cell therapy in China: 2020 update. Cell Mol Immunol. 2021;18(4):792–804. doi: 10.1038/s41423-020-00555-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Sterner RM, Sakemura R, Cox MJ, et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019;133(7):697–709. doi: 10.1182/blood-2018-10-881722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–38. doi: 10.1016/j.bbmt.2018.12.758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.He H, Liao Q, Zhao C, et al. Conditioned CAR-T cells by hypoxia-inducible transcription amplification (HiTA) system significantly enhances systemic safety and retains antitumor efficacy. J Immunother Cancer. 2021;9(10):e002755. doi: 10.1136/jitc-2021-002755. [DOI] [PMC free article] [PubMed] [Google Scholar]

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Data Availability Statement

All data supporting the findings of this review are available within the manuscript and its cited sources.

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