Li Xu

Background & Aims: While thermal ablation is a standard curative-intent modality for early-stage hepatocellular carcinoma (HCC), there is an unmet need to explore strategies aimed at reducing tumor recurrence. We designed this exploratory trial to investigate the safety, efficacy, and immunological impact of combining perioperative immunotherapy with thermal ablation.Methods: In this single-arm phase II trial (NCT04652440), participants with one or two HCC lesions measuring 2-5 cm received thermal ablation with a short-course peri-ablation regimen (1 cycle pre- and 3 cycles post-ablation) of tislelizumab 200 mg every 3 weeks. Patients were permitted to undergo a single re-ablation within 12 weeks in the event of an incomplete response. The primary endpoints were safety and tolerability. Secondary endpoints included complete response at first imaging assessment (CR1), local recurrence rate (LRR), distant metastasis rate (DMR), disease-free survival (DFS), and overall survival (OS).Results: Thirty participants were enrolled between December 2020 and August 2023, and 26 patients (86.7%) completed protocol-specified treatment. Grade 3 treatment-related adverse events occurred in 23 patients (76.7%), predominantly transient ablation-related transaminase elevations. No treatment-related deaths occurred. CR1 was achieved in 28 patients (93.3%), LRR was 53.3% and DMR was 0%. At a median follow-up of 36.3 months, the 1- and 2- year DFS rate were 72.9% (95% confidence interval [95% CI], 58.5-90.9%) and 47.3% (95% CI, 31.9-70.2%), respectively, with a median DFS of 20.2 months. The 1- and 2- year OS rate were 100% (95% CI, 100-100%) and 95.5% (95% CI, 87.1-100%). In parallel murine models, pre-ablation PD-1 blockade significantly increased intratumoral CD8⁺ T-cell infiltration and antitumor efficacy.Conclusion: Short-course peri-ablation tislelizumab combined with curative-intent thermal ablation was feasible, tolerable, and showed substantial clinical benefit in early-stage HCC, supporting further evaluation in randomized trials.

Immunotherapies achieve durable responses in several cancers but show limited efficacy in refractory hepatocellular carcinoma (HCC). The mechanisms by which hepatoma cells evade immune recognition and limit immune checkpoint blockade (ICB) efficacy are incompletely defined. Here, we identified tumor-intrinsic tescalcin (TESC) as a previously unrecognized phagocytic checkpoint that contributes to immune evasion and ICB resistance in HCC. Mechanistically, H3K4 methylation drove TESC expression in hepatoma cells, facilitating cytosolic Ca ²⁺ buffering and attenuating endoplasmic reticulum (ER) stress–induced calreticulin (CALR) plasma membrane exposure, an essential “eat-me” signal. Consequently, this process abrogated membrane CALR-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and DCs, thereby impairing antigen presentation and subsequent T cell activation. Clinically, we found that elevated H3K4me3-TESC signaling was a promising prognostic biomarker for a poor ICB response in HCC. Importantly, in vivo disruption of this axis restored APC phagocytic function and enhanced the antitumor effects of ICB therapy. Therefore, targeting TESC-driven immune escape and its underlying epigenetic regulation may restore APC function and offer a precise therapeutic strategy to enhance immunotherapeutic efficacy in HCC.

Supplementary Table 4. Immune-related adverse events.

Purpose:Immune checkpoint inhibitor (ICI)–related trials in hepatocellular carcinoma (HCC) have strict restrictions on hepatitis B (HBV) DNA load because of HBV reactivation. This study aimed to compare the HBV reactivation between patients with HCC with low or high HBV DNA loads receiving ICIs and antiviral therapy.Patients and Methods:This prospective observational study (NCT04680598) recruited hepatitis B surface antigen–positive patients with HCC who received concurrent antiviral therapy with initial ICI treatment. Participants were divided into HBV DNA–low (≤500 IU/mL) and HBV DNA–high (>500 IU/mL) groups. The primary endpoint was the HBV reactivation rate.Results:Between December 25, 2020, and February 23, 2024, 356 and 659 participants were enrolled in the HBV DNA–low and HBV DNA–high groups. The HBV DNA–high group included significantly higher proportions of patients with hepatitis Be antigen positivity (24.1% vs. 7.0%, P < 0.001), albumin–bilirubin grade 2 to 3 (49.9% vs. 33.7%, P < 0.001), and Barcelona Clinic Liver Cancer stage C (83.3% vs. 72.5%, P < 0.001). The HBV reactivation rate (4.5% vs. 6.1%, relative risk, 1.24; 95% confidence interval, 0.81–1.89; P = 0.29), frequencies of HBV reactivation–associated hepatitis (1.7% vs. 2.3%, P = 0.53), and interruptions in ICI treatment (25.8% vs. 30.5%, P = 0.12) were comparable in the HBV DNA–low group and HBV DNA–high group.Conclusions:There was no significant difference in the risk of HBV reactivation between patients with HCC with HBV DNA ≤500 IU/mL and those with HBV DNA >500 IU/mL when treated with ICIs and concurrent antiviral prophylaxis.

Supplementary Table 8: Representativeness of study participants

Supplementary Figure 2. Survival analysis. Kaplan‒Meier curves of overall survival of patients in HBV DNA-low and HBV DNA-high groups, using (A) 1000 IU/mL and (B) 2000 IU/mL as cutoff, respectively.

Supplementary Table 1. Detailed characteristics of participants with HBV reactivation.

Supplementary Table 6. Tumor response in patients received ICIs monotherapy or combination therapy

Supplementary Table 3. Treatment-related adverse events.