This retrospective cohort study enrolled consecutive patients diagnosed with unresectable HCC, classified as Barcelona Clinic Liver Cancer (BCLC) stage B or C, at a single tertiary center between January 2018 and June 2023. Inclusion criteria were Child-Pugh class A or B liver function, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, no prior exposure to systemic therapy or TACE, and the presence of at least one measurable intrahepatic lesion according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) (22). Exclusion criteria included non-TACE indications, active autoimmune diseases or ongoing immunosuppressive therapy, incomplete clinical or imaging follow-up data, and severe cardiovascular comorbidities such as uncontrolled hypertension or New York Heart Association class III/IV heart failure. Patients were divided into either the systemic therapy group (STG) or the combination therapy group (CTG), based on whether they received treatment without or with TACE. The grouping of patients (STG vs. CTG) was primarily determined by whether they met the clinical criteria for TACE treatment (e.g., liver function, tumor burden, portal vein invasion status, etc.), rather than random assignment. The patient screening flowchart is presented in Figure 1 .

Patients in the CTG received standard TACE using a lipiodol-based chemotherapeutic emulsion (containing pirarubicin, 30–50 mg; lobaplatin, 30–50 mg; and lipiodol, 2–15 ml), followed by embolization with microspheres and gelatin sponge particles (100–300 μm) (23). The chemotherapeutic agent dosage was adjusted according to tumor size and liver function. Repeat TACE procedures were performed on an on-demand basis upon imaging evidence (contrast-enhanced CT or MRI) of active tumor or intrahepatic recurrence. All TACE procedures were conducted by interventional radiologists at our center with at least 5 years of experience. Under DSA guidance, selective catheterization of tumor-feeding arteries was performed, followed by embolization until stasis of contrast flow. Repeat TACE sessions were administered for residual or recurrent lesions, with intervals ≥4 weeks between procedures. Post-procedure management included hydration, analgesics, and monitoring for embolization-related complications.

In the STG, patients received intravenous tislelizumab (200 mg every 3 weeks) combined with oral TKIs: sorafenib (400 mg twice daily), lenvatinib (8 mg/day for body weight <60 kg or 12 mg/day for ≥60 kg), regorafenib (80, 120 or 160 mg once daily for 3 weeks followed by 1 week off), apatinib (500 or 750 mg once daily), or donafenib (200 mg twice daily); with TKI dose reductions permitted for grade ≥3 adverse events (AEs). The CTG group initiated the same systemic regimen (tislelizumab plus TKIs) within 7 days after the first TACE session, with subsequent TACE cycles synchronized to systemic therapy and temporary TKI interruption (≤7 days) during TACE procedures. Treatment protocols included dose adjustments for TKIs (50% reduction for grade 3 AEs and discontinuation for grade 4 events) and permanent discontinuation of tislelizumab for unresolved grade ≥3 immune-related AEs despite corticosteroid therapy. Systemic therapy was continued until disease progression, intolerable toxicity, or patient withdrawal.

Tumor response was evaluated using contrast-enhanced CT or MRI at baseline and every 8 (± 1) weeks thereafter. The radiologists involved in assessing tumor response were not formally blinded to the treatment groups. All radiographic assessments were conducted according to the standardized mRECIST criteria. The scans were reviewed independently by two experienced radiologists, with any discrepancies resolved by a third senior radiologist to reach a consensus. Clinical and laboratory variables collected included: extrahepatic spread, portal vein tumor thrombus, serum alpha-fetoprotein (AFP), and gamma-glutamyl transferase (GGT) levels. Safety monitoring adhered to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, with specific documentation of TACE-related complications.

Overall survival (OS) was defined as the time from treatment initiation to death from any cause. Progression-free survival (PFS) was measured as the time to radiologic progression or death. Survival curves were generated using the Kaplan-Meier method and compared via log-rank test. Univariate and Multivariate Cox regression analyses were performed for all baseline variables, including sex, age, surgical resection, TKI agents (sorafenib, regorafenib, apatinib, donafenib; reference: lenvatinib), TACE, etiology, extrahepatic spread, tumor diameter, tumor number, portal vein tumor thrombus, Child-Pugh class, BCLC stage, MELD score, AFP, platelet count, prothrombin time (PT), international normalized ratio (INR), albumin, serum creatinine (Scr), GGT, cholinesterase, total bilirubin, hemoglobin, and lymphocyte count. The cut-off values were based on either established clinical standards (as for AFP) or ROC-derived values (as for GGT). To minimize the potential influence of confounding factors and reduce selection bias affecting OS and PFS, baseline patient characteristics between the two groups were matched using 1:1 propensity score matching (PSM). The matching variables included sex, age, surgical resection, type of TKIs, hepatitis status, extrahepatic spread, tumor diameter, tumor number, BCLC stage, portal vein tumor thrombus, Vp type, Child-Pugh class, MELD score, AFP level, and platelet count. Treatment effect heterogeneity was evaluated using likelihood ratio tests. All analyses were conducted using R software (version 4.2.2) and SPSS (version 26.0). A two-sided P-value <0.05 defined statistical significance.

This retrospective analysis included 283 consecutive patients with unresectable HCC treated between January 2018 and June 2023, comprising 185 patients receiving combination therapy (tislelizumab + TKIs + TACE) and 98 receiving systemic therapy alone (tislelizumab + TKIs). Baseline characteristics were well-balanced between groups (p >0.05 for all comparisons): The cohort had a median age of 58 years (interquartile range [IQR] 52–65), with male predominance (85.5%) and hepatitis B as the primary etiology (85.9%). Key clinical features including extrahepatic spread (36.2% vs. 48.0%, p=0.055), portal vein tumor thrombus (34.1% vs. 34.7%, p=0.914), AFP ≥400 ng/mL (33.0% vs. 27.6%, p=0.348), tumor diameter ≥5cm (56.2% vs. 52.0%, p=0.502), and BCLC stage distribution (Stage B: 38.9% vs. 37.8%; Stage C: 61.1% vs. 62.2%, p=0.848) showed no statistically significant differences. No significant baseline differences were observed between the two groups ( Table 1 ). After PSM, each group contained 96 individuals, and the baseline differences between them were significantly reduced, as detailed in Supplementary Table 1 .

With a median follow-up of 28.6 months (IQR 18.8–34.7), the combination therapy group demonstrated significantly superior survival outcomes compared to systemic therapy alone. After PSM, the median OS was 22.5 months (95% confidence interval [CI] 19.0–34.4) versus 14.0 months (95% CI 12.1–18.6), corresponding to a 47% reduction in mortality risk (hazard ratio [HR] 0.53, p<0.001) ( Figure 2 A ). The median PFS was significantly prolonged in the combination group (14.6 months, 95% CI 12.1–19.1 vs. 9.5 months, 95% CI 7.8–12.5; HR 0.64, p<0.001) ( Figure 2 B ).

Multivariate analysis of the entire cohort identified five independent predictors of poor OS: age <60 years (HR 1.503, 95% CI 1.109–2.036; p=0.008), extrahepatic spread (HR 2.114, 95% CI 1.550–2.884; p<0.001), portal vein tumor thrombus (HR 1.480, 95% CI 1.083–2.023; p=0.014), AFP ≥400 ng/mL (HR 2.317, 95% CI 1.679–3.198; p<0.001), and elevated GGT (cut-off value =107.003; per-unit increase HR 1.002, 95% CI 1.001–1.002; p<0.001). Details are shown in Table 2 . Subgroup analysis within the combination therapy group revealed maximal survival benefit in patients aged ≥60 years (HR 0.593, 95% CI 0.397–0.886; p=0.011), without extrahepatic spread (HR 0.578, 95% CI 0.381–0.877; p=0.010), AFP <400 ng/mL (HR 0.493, 95% CI 0.326–0.746; p=0.001), and normal GGT levels (cut-off value =97.589; per-unit decrease HR 0.999, 95% CI 0.998–1.000; p=0.037). Details are shown in Table 3 .

Safety analysis showed significantly higher rates of all-cause adverse events in the combination therapy group compared to systemic therapy alone (79.6% vs. 67.0%, p=0.021), with notably increased grade ≥3 events (23.5% vs. 14.1%, p=0.038). The combination group experienced predominantly liver-related toxicities, hematological abnormalities, and TACE-specific complications including post-embolization syndrome. Treatment discontinuation rates were comparable for tislelizumab (10.2% vs. 6.5%, p=0.285) and TKIs (32.7% vs. 27.0%, p=0.347). Summary of details are shown in Table 4 . TACE-related AEs occurred in 46.5% of CTG patients, with Grade 3 events in 8.7% and one Grade 4 event (0.5%). Tislelizumab-related AEs were reported in 28.7% of CTG and 40.8% of STG patients, with Grade 3 events in 9.7% and 15.3%, respectively. TKI-related AEs occurred in 33.5% of CTG and 42.9% of STG patients, with Grade 3 events in 6.5% and 10.2%, respectively ( Supplementary Table 2 ). In the STG, the most common any-grade AEs were fatigue (45.9%), pyrexia (40.8%), increased AST (35.7%), and increased ALT (32.7%). Grade 3 AEs were observed in 23.5% of patients, with no Grade 4 or 5 events ( Supplementary Table 3 ). In the CTG, the most frequent any-grade AEs were increased AST (40.5%), increased ALT (37.8%), fatigue (37.8%), and abdominal pain (36.8%). Grade 3 AEs occurred in 14.1% of patients, with one Grade 4 abdominal pain event (0.5%). No Grade 5 events were reported in either group ( Supplementary Table 4 ).