HCC complicated by portal vein tumor thrombus (PVTT) frequently exhibits concurrent hepatic arteriovenous shunting, which impedes effective embolization of the thrombus-associated vasculature during TACE. Consequently, TACE demonstrates suboptimal therapeutic efficacy in this subset of patients with HCC, representing a persistent clinical challenge in HCC management. A novel therapeutic paradigm integrating TACE with portal vein stenting and intra-luminal I-125 brachytherapy, pioneered through seminal contributions by Chinese researchers, has shown marked efficacy in patients with HCC and PVTT (15). In cases of PVTT involving the main portal vein or primary branches, the deployment of I-125-loaded stents or seed-releasing stents achieves dual objectives, namely, the alleviation of portal hypertension, the restoration of physiological hepatopetal flow, the optimization of hepatic functional reserve and the enablement of subsequent TACE by thrombus control (16). Evidence indicates that TACE combined with I-125-impregnated stents or radioactive seed-releasing stents enhances stent patency and extends OS time in patients with HCC and main portal vein thrombosis (17). A study (18) demonstrated that TACE-I-125 brachytherapy synergy achieves superior tumor response rates and survival outcomes compared with TACE monotherapy in complex HCC cases. Chen et al (19) demonstrated that the combination of I-125 brachytherapy with TACE resulted in a significant prolongation of median OS and progression-free survival (PFS) times, alongside a markedly higher ORR compared with TACE monotherapy. I-125 brachytherapy has been established as a safe and efficacious adjunct to minimally invasive locoregional therapies in HCC, with a favorable safety profile (20). Therefore, for patients with surgically unresectable primary liver cancer complicated by PVTT, if the tumor thrombus has not involved the main trunk and postoperative hepatic blood flow is expected to recover, this combination therapy can be adopted.

External beam radiotherapy (EBRT), a non-invasive locoregional therapeutic modality, employs precisely calibrated ionizing radiation to selectively eradicate neoplastic cells. Ionizing radiation directly or indirectly damages macromolecules, impairing their function and triggering biological effects (21). A study (22) demonstrated that the combination of radiotherapy with TACE in patients with advanced HCC resulted in enhanced tumor control rates and superior survival outcomes relative to TACE monotherapy, with no statistically significant differences in adverse event rates observed between the two regimens. For unresectable PVTT, the combination of radiotherapy and TACE is now widely regarded as the preferred therapeutic regimen, with clinical studies (23–25) having established its superior efficacy in comparison to monotherapy with radiotherapy, TACE or sorafenib.

A comprehensive meta-analysis (26) demonstrated that the integration of TACE with radiotherapy in patients with advanced HCC and PVTT resulted in superior short-term clinical responses and enhanced OS outcomes [improved ORR: odds ratio, 4.22; 95% confidence interval (CI), 3.07–5.80; P<0.001; and OS: hazard ratio (HR), 0.69; 95% CI, 0.57–0.83; P=0.001], without a statistically significant increase in treatment-related adverse events, as systematically evaluated across diverse patient cohorts. Shui et al (27) studied 70 patients with HCC and PVTT and found that the combination of SBRT and TACE significantly prolonged OS time (12 vs. 3 months) compared with SBRT alone without subsequent TACE. Wu et al (28) showed that three-dimensional conformal radiation therapy combined with TACE may provide a better OS time than either technique alone in patients with HCC and PVTT. Radiotherapy has been shown to effectively downstage advanced HCC, particularly in managing thrombus formation. Even in cases involving thrombi localized to the main portal vein or its first-order branches, radiotherapy has been observed to induce complete thrombus necrosis, thereby promoting tumor downstaging. Consequently, the combination of TACE and radiotherapy enhances both tumor and thrombus control, thereby increasing the likelihood of successful downstaging (29). Collectively, the integration of TACE with radiotherapy has been shown to confer marked survival benefits and superior clinical efficacy in the treatment of HCC.

Ablation therapy encompasses a diverse array of minimally invasive techniques, such as radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, high-intensity focused ultrasound, irreversible electroporation and percutaneous ethanol injection. The combination of TACE and ablation therapy demonstrates synergistic therapeutic advantages by collectively addressing the intrinsic limitations of each monotherapy (30). This multimodal approach significantly reduces tumor progression and recurrence rates, diminishes the necessity for repeated TACE sessions, mitigates chemotherapy-induced hepatic injury and resistance, enhances patient quality of life and prolongs OS time (31). This combined strategy demonstrates superior clinical outcomes compared with TACE or ablation monotherapy in patients with unresectable solitary or multifocal tumors (3–7 cm) classified as China Liver Cancer (CNLC) stages (12) Ib-IIa (32). In cases of CNLC stage Ia tumors located in anatomically challenging regions (e.g., adjacent to the diaphragmatic dome or critical intra-/extrahepatic vasculature), standalone ablation exhibits limited efficacy; however, adjunctive pre-ablation TACE enhances lesion demarcation, thereby facilitating precise targeting and comprehensive tumor eradication while minimizing procedural complications (32).

A retrospective cohort study involving 46 patients with large HCC (maximal diameter >5 cm) undergoing combined TACE-RFA therapy demonstrated favorable safety and clinical efficacy, with complete remission (CR) and partial remission (PR) rates of 82.6 and 17.4%, respectively, at 1-month follow-up. Cumulative local tumor progression rates at 1-, 2- and 3-year intervals were 4.3, 13.1 and 30.4%, respectively, while corresponding OS rates reached 89.1, 71.7 and 56.5% (33). A systematic meta-analysis evaluated the efficacy of TACE combined with MWA vs. TACE monotherapy in patients with early-to-intermediate-stage HCC (tumor diameter >5 cm). The combination therapy (TACE + MWA) demonstrated that, compared with TACE alone, TACE + MWA resulted in significantly higher 1-, 2- and 3-year OS rates [1-year OS: risk ratio (RR), 1.36; 95% CI, 1.28–1.44; P<0.001; 2-year OS: RR, 1.56; 95% CI, 1.40–1.74; P<0.001; and 3-year OS: RR, 2.07; 95% CI. 1.67–2.57; P<0.001] (34). Furthermore, combination therapy achieves enhanced local tumor control in anatomically critical zones (e.g., peribiliary or perivascular regions) among patients with CNLC stage IIb-IIIb, thereby reducing the likelihood of tumor invasion into adjacent vital structures (35).

The therapeutic efficacy of TACE is constrained by portal venous blood flow, resulting in incomplete tumor necrosis and acquired chemoresistance following repeated procedures. HAIC administers chemotherapeutic agents intra-arterially to target lesions, achieving sustained high-concentration drug exposure within tumor vasculature. This approach enhances tumoricidal efficacy, demonstrating significantly higher ORRs than systemic chemotherapy or sorafenib monotherapy (36).

In cases of multifocal HCC involving distinct hepatic segments or tumors with a dual arterial supply, neither HAIC nor TACE monotherapy may suffice. Combined therapy achieves synergistic antitumor effects through complementary mechanisms. Following TACE, adjunctive HAIC exposes viable residual tumor tissue to cytotoxic drug concentrations, thereby eradicating residual malignant cells, reducing embolization frequency and mitigating procedure-related complications (37). Li et al (37) reported that TACE-HAIC combination therapy significantly improved ORRs (14.6 vs. 2.4%; P=0.107) compared with TACE alone in unresectable HCC cohorts, with comparable incidence of grade ≥3 adverse events. The TACE-HAIC regimen confers enhanced clinical benefits in patients with HCC and bulky tumors (>5 cm diameter), particularly in terms of locoregional control and survival outcomes (38). In HCC with PVTT (particularly main trunk involvement), bulky tumors, high-flow arteriovenous shunts refractory to TACE or acquired TACE resistance, the integration of modified FOLFOX regimen-based HAIC potentiates TACE efficacy through chemosensitization (39).

TACE-induced ischemic and hypoxic microenvironments upregulate vascular endothelial growth factor receptor (VEGFR) expression, thereby promoting compensatory angiogenesis and facilitating residual tumor proliferation and metastatic dissemination (40). The combinatorial regimen of TACE and anti-angiogenic targeted agents exerts synergistic antitumor effects through dual modulation of tumor burden reduction and angiogenesis suppression. In advanced HCC, however, the extensive tumor burden compromises single-agent therapeutic efficacy, yielding an ORR of ~20% in monotherapy cohorts (41).

The integration of sorafenib, a first-line multikinase inhibitor for HCC, with TACE significantly enhances OS and PFS times in patients with unresectable HCC (42). The phase II TACTICS trial demonstrated that TACE-sorafenib combination therapy markedly extended median PFS time (25.2 vs. 13.5 months; P=0.006), time to untreatable progression (26.7 vs. 20.6 months; P=0.02), and 1- and 2-year OS rates (96.2 vs. 82.7% and 77.2 vs. 64.6%) compared with TACE monotherapy (42). TACE potentiates intratumoral drug accumulation, thereby augmenting the antiproliferative and proapoptotic effects of sorafenib. The dual mechanism of sorafenib, namely direct tumor cytotoxicity and angiogenesis inhibition, effectively counteracts TACE-induced revascularization. The OPTIMIS real-world study demonstrated that the early integration of sorafenib into therapeutic regimens resulted in a significant prolongation of OS time relative to delayed or absent combination therapy (43). Consequently, the combination of sorafenib with TACE is recognized as a clinically recommended regimen, offering both efficacy and a favorable safety profile.

Regorafenib, a second-line multikinase inhibitor with enhanced VEGFR-2/3 inhibitory potency and broader antiangiogenic activity compared with sorafenib, is indicated for sorafenib-refractory HCC. The phase III RESORCE trial established that sequential regorafenib therapy, administered subsequent to sorafenib treatment failure, achieved a median OS time of 10.6 months (95% CI, 9.1–12.1) and conferred a statistically significant survival benefit, with a HR of 0.63 (95% CI, 0.50–0.79; one-sided P<0.0001) (44). In second-line settings, regorafenib-TACE combination therapy exhibited a favorable ORR (42.3%) and disease control rate (DCR: 66.1%), with grade ≥3 adverse events limited to 15.3% of patients (45).

Lenvatinib, an oral multikinase inhibitor, exerts potent antitumor activity through the dual blockade of fibroblast growth factor receptor 1–4 and VEGFR1-3 signaling pathways (46). Preclinical HCC models further reveal its immunomodulatory properties via programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis suppression and tumor-associated macrophage polarization (47). However, monotherapy often leads to resistance, necessitating combination therapy. The multicenter LAUNCH trial demonstrated that lenvatinib-TACE combination therapy significantly improved median OS time (17.8 vs. 11.5 months; HR, 0.45; P<0.001), PFS time (10.6 vs. 6.4 months; HR, 0.43; P<0.001) and ORR (54.1 vs. 25.0%; P<0.001) vs. lenvatinib monotherapy (48). A retrospective study showed an 11.1% surgical conversion rate, a 5.5-month median PFS time and a 14.1-month median OS time for lenvatinib plus TACE in PD-L1-positive unresectable HCC (49). Japanese researchers suggest considering lenvatinib upfront followed by TACE as needed for patients with intermediate stage HCC beyond up-to-7 criteria (sum of the size of the largest HCC tumor in cm and the number of tumors) (50). Sequential lenvatinib and TACE show clinical advantages in advanced HCC (51).

Apatinib, a next-generation VEGFR-2 inhibitor exhibiting 10-fold greater binding affinity than sorafenib (52), has emerged as a promising adjunct to TACE regimens. A clinical study demonstrated that the combination of TACE and apatinib significantly prolonged median PFS time compared with TACE monotherapy (median PFS was 6.83 months with TACE + apatinib and 3.81 months with TACE alone), while maintaining a favorable tolerability profile (53).

Anti-VEGF monoclonal antibodies, including bevacizumab and biosimilars, bind to VEGF-A, inhibiting angiogenesis. A retrospective study of drug-eluting microsphere TACE plus bevacizumab in unresectable HCC cohorts demonstrated an ORR of 14.2%, a DCR of 100%, a median OS time of 13.0 months and absence of grade ≥3 toxicity (54). Excessive bevacizumab dosing may induce pathological tumor vessel normalization, paradoxically fostering hypoxia-mediated therapeutic resistance and compromising TACE-mediated ischemic cytotoxicity (55).

HCC immunotherapy primarily utilizes immune checkpoint inhibitors (ICIs), which exhibit synergistic potential in combination with TACE to enhance clinical outcomes. TACE induces the release of tumor-associated antigens, thereby triggering immunogenic cell death and initiating antitumor immune responses. This process augments antigen-specific T lymphocyte infiltration, upregulates immunomodulatory factors and potentiates the efficacy of ICIs (56). A clinical study (57) demonstrated that TACE exerts immune-activating effects, providing robust support for the therapeutic rationale underlying TACE-ICI combination strategies. The phase II IMMUTACE trial (58) met its primary endpoint of ORR and demonstrated a favorable safety profile, thus corroborating the clinical efficacy of TACE-ICI combination therapy. Combination therapy of TACE with anti-PD-1 inhibitors demonstrated significant prolongation of both PFS and OS times in advanced HCC cohorts (59). One clinical trial demonstrated that TACE combined with pembrolizumab notably prolonged survival time among patients with sorafenib-refractory HCC (60).

Cytokine-induced killer (CIK) cells exhibit potential for eradicating micrometastases, while dendritic cells (DCs) substantially augment CIK cell cytotoxicity through antigen-presentation mechanisms (61). The synergistic integration of DCs and CIK cells represents an emerging cell-based immunotherapeutic strategy for HCC. A comprehensive meta-analysis (62) demonstrated the superiority of TACE-DC-CIK combination therapy over TACE monotherapy in promoting an improved overall response, for half-year (RR, 1.16; 95% CI, 1.06–1.26; P=0.008), 1-year (RR, 1.22; 95% CI, 1.10–1.36; P=0.002) and 2-year (RR, 1.39; 95% CI, 1.16–1.66; P=0.004) OS, median OS (OR, 1.35; 95% CI, 1.04–1.66; P<0.00001) and PFS (RR, 1.9; 95% CI, 1.58–2.23; P<0.00001) in patients with HCC.

The integration of targeted therapy and immunotherapy synergistically potentiates the therapeutic efficacy of TACE. Targeted agents inhibit VEGF-mediated signaling pathways, thereby facilitating effector immune cell infiltration, counteracting tumor immune evasion, amplifying antitumor immunity and mitigating recurrence risks associated with post-TACE neoangiogenesis (63). The CHANCE001 trial (64), a multicenter real-world cohort study evaluating TACE combined with targeted-immunotherapy regimens in HCC, demonstrated that this multimodal approach significantly improved PFS time, OS time and ORR vs. TACE monotherapy in advanced HCC cohorts, while maintaining an acceptable safety profile.

Recent clinical evidence (65) indicates that TACE combined with sorafenib and ICIs confers prolonged PFS and OS times relative to TACE-sorafenib dual therapy. A retrospective cohort analysis (66) revealed that lenvatinib combined with TACE and PD-1 inhibitors demonstrated synergistic efficacy and safety in advanced HCC, with significantly superior PFS time, OS time, ORR and DCR compared with TACE-lenvatinib combination therapy.

In the context of conversion therapy for unresectable HCC, the combination of TACE with TKIs and PD-1 inhibitors achieved an ORR of 81.8% (18/22), a DCR of 90.9% (20/22) and a surgical conversion rate of 45.5% (10/22), including three cases attaining complete pathological remission post-resection (67). A retrospective investigation (68) of TACE combined with lenvatinib and PD-1 inhibitors in unresectable HCC revealed early tumor responses in 72.3% (68/94) of the cohort, accompanied by elevated surgical conversion rates and extended median PFS and OS times within this population.

The integration of TCM with TACE exhibits synergistic therapeutic potential in the management of HCC. Accumulating clinical evidence (69,70) indicates that TACE combined with TCM adjunctive therapy enhances therapeutic outcomes, augments immune surveillance and mitigates adverse events associated with TACE monotherapy. Huaier Granule, a TCM formulation, has been shown to ameliorate clinical symptoms, potentiate immune function, suppress tumor recurrence and prolong OS time in patients with HCC who are undergoing TACE (71).

In patients with HCC and underlying hepatitis B virus or hepatitis C virus infections, systematic integration of antiviral therapy with TACE is imperative to optimize therapeutic outcomes and long-term prognosis, as part of a pathophysiology-driven strategy (12,72). A clinical trial (72) demonstrated that chemo-lipiodolization was significantly correlated with a higher incidence of hepatitis attributed to HBV reactivation compared with other treatments (21.7 vs. 1.6%; P<0.001). Transarterial chemo-lipiodolization can reactivate patients with HBV and HBeAg-positive HCC; therefore, receiving chemo-lipiodolization should be closely monitored for HBV reactivation.