Dual TIGIT and PD-1 blockade in immunotherapy-refractory hepatocellular carcinoma: a signal beyond resistance?

The therapeutic landscape for advanced hepatocellular carcinoma (HCC) has rapidly shifted over the last several years, driven primarily by the successful adoption of immune checkpoint inhibitors (ICIs) into first-line therapy (1,2). This has led to improved survival rates and better overall patient outcomes. The combination of programmed cell death protein 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) blockade with anti-vascular endothelial growth factor (VEGF) agents has redefined the standard of care (3), while regimens including cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibition have further expanded immunotherapeutic strategies for selected patients (4). Despite these advances, a major clinical dilemma remains unresolved: how should clinicians manage patients whose tumours progress after anti-PD-1/PD-L1 treatment? This challenge is becoming increasingly urgent as immunotherapy is administered earlier in the disease course—including in downstaging, conversion, and peri-transplant settings—resulting in a growing proportion of patients with tumours refractory to ICI-based therapies (5). Current post-ICI treatment options for HCC remain limited. Tyrosine kinase inhibitors (TKIs) are frequently used in this setting, yet they provide modest response rates and are often associated with clinically significant toxicity, particularly in patients with cirrhosis and compromised liver function (6). Consequently, outcomes after failure of first-line immunotherapy remain suboptimal, highlighting the need for alternative strategies capable of overcoming immunotherapy resistance. Among emerging targets, the T-cell immunoglobulin and ITIM domain (TIGIT) pathway has gained attention as a potential mediator of immune escape following PD-1 blockade (7). TIGIT is a key inhibitory immune checkpoint receptor expressed on exhausted CD8⁺ T cells and natural killer (NK) cells. Through interactions with its ligands, CD155 and CD112, TIGIT suppresses T-cell activation, dampens cytotoxic function, and alters antigen-presenting cell signalling within the tumour microenvironment (8).

Preclinical studies have demonstrated that TIGIT expression is frequently upregulated following PD-1 inhibition, suggesting that it may function as a compensatory checkpoint limiting the durability of PD-1-directed therapies (9). In HCC, where chronic inflammation and immune dysfunction are central to disease biology, TIGIT has been implicated in T-cell exhaustion and impaired antitumor immunity. Dual inhibition of TIGIT and PD-1 has shown synergistic activity in preclinical HCC models, restoring cytotoxic T-cell function and enhancing tumour control (10). However, clinical data on TIGIT-targeting strategies in HCC have been inconsistent, raising questions regarding optimal trial design, patient selection, and antibody engineering.

The phase 2 LIVERTI trial directly addresses several of these uncertainties by evaluating dual TIGIT-PD-1 blockade specifically in patients with immunotherapy-refractory HCC (11). Unlike previous studies that examined TIGIT inhibitors in treatment-naive patients or in frontline combination regimens, Hsiehchen and colleagues tested domvanalimab, an Fc-silent anti-TIGIT antibody, combined with the anti-PD-1 agent zimberelimab in patients with documented failure of prior anti-PD-1/PD-L1 therapy, including regimens containing VEGF, CTLA-4, or LAG-3 blockade. The choice of an Fc-silent TIGIT antibody is a critical distinction from earlier agents, as Fc-competent antibodies may inadvertently deplete activated effector T cells or regulatory T-cell subsets through antibody-dependent cellular cytotoxicity, potentially limiting efficacy or increasing toxicity (12). This investigator-initiated, open-label basket trial, conducted at two clinical sites, was initially designed to include two independent single-arm cohorts—one for advanced HCC and one for biliary tract cancers—each planned to enrol 29 evaluable patients. In the first published report, only the HCC cohort had completed accrual, enrolling 29 patients with histologically confirmed HCC who were refractory to or had relapsed after prior anti-PD-1/L1 therapy administered in any line.

Clinically, domvanalimab plus zimberelimab achieved a confirmed objective response rate (ORR) of 17.2% [95% confidence interval (CI), 5.8–35.8%], including one complete and four partial responses, and a disease control rate of 62.1%. The 6-month progression-free survival (PFS) rate was 40.4% (95% CI, 21.6–58.5%), with a median PFS of 4.4 months (11). Although the primary endpoint of ORR was not formally met, the observed response remains meaningful in the context of immunotherapy-refractory HCC (6), where second-line therapies such as TKIs typically achieve ORRs of 4–10%. These results suggest relevant antitumour activity in a heavily pre-treated population. Waterfall and PFS analyses revealed that a subset of patients achieved deep and durable tumour regressions. Nonetheless, the modest sample size limited correlations with clinical or genomic features, and follow-up was insufficient to assess survival outcomes.

Notably, responses occurred only in patients with primary resistance, supporting distinct biological states (13). One explanation relates the TIGIT pathway. TIGIT, expressed on exhausted CD8⁺ T cells, regulatory T cells, and NK cells, competes with CD226 for CD155 binding, suppressing cytotoxic function. In primary resistance, tumour-reactive T cells may persist but remain inhibited, and dual TIGIT/PD-1 blockade may restore antitumour immunity. By contrast, acquired resistance may involve mechanisms such as antigen loss, impaired antigen presentation, or immune exclusion, which are unlikely to be overcome by additional checkpoint inhibition. This suggests that TIGIT inhibition may preferentially benefit tumours with primary rather than acquired resistance.

The safety profile of domvanalimab plus zimberelimab was generally manageable (11). Treatment-related adverse events (TRAEs) were reported in 58.6% of cases, while grade 3–4 TRAEs were observed in only 13.8%, a rate that appears numerically lower than historical data (6). Immune-related toxicities were manageable, and treatment discontinuation due to adverse events (AEs) was required in three patients. Hepatic decompensation occurred in 5 patients (17.2%) but was primarily attributed to disease progression rather than treatment, underscoring the regimen’s tolerability in patients with compromised liver function. However, these findings are not directly comparable to first-line ICI studies, owing to differences in patient populations and the exclusion of individuals with severe prior immune-related toxicities. Consequently, it remains unclear whether patients who previously experienced AEs with TKIs or ICIs would similarly develop toxicities when treated with TIGIT-PD-1 blockade. While these findings require confirmation in larger cohorts, they suggest that this dual blockade may represent a tolerable option for patients who are frail or unable to receive VEGF-targeted therapies.

Beyond clinical outcomes, LIVERTI provides valuable translational insights by integrating circulating tumour DNA (ctDNA) analysis. Using an 83-gene tumour-agnostic panel, investigators assessed ctDNA from peripheral blood samples at baseline and post-cycle two during treatment. Baseline ctDNA alterations—most commonly involving TERT, TP53, and CTNNB1—did not correlate with radiological response (11). In contrast, early-onset ctDNA changes were strongly associated with clinical outcomes. ctDNA levels declined in most responders, often by more than 50%, whereas they increased in patients with stable or progressive disease. Importantly, ctDNA trajectories mirrored disease evolution in patients who initially responded and subsequently progressed (11). These findings suggest that ctDNA may provide greater pharmacodynamic sensitivity than AFP, particularly in AFP-non-producing HCC, and reductions in specific genomic alterations raise the hypothesis that certain molecular subclones may be particularly susceptible to TIGIT-PG-1 blockade. The weak correlation between AFP and ctDNA observed in LIVERTI underscores this point. While exploratory, these results support further investigation of ctDNA as an early response marker and as a tool for studying tumour evolution under immune-selective pressure (14).

LIVERTI also helps clarify why previous TIGIT-targeting studies in HCC have yielded inconsistent results. Although tiragolumab-based combinations showed encouraging activity in early phase trials, this did not translate into success in phase 3 (IMbrave152/SKYSCRAPER-14). The signal observed in LIVERTI remains noteworthy, as it was generated in a biologically distinct population with prior anti-PD-1/PD-L1 failure and using an Fc-silent anti-TIGIT antibody.

These findings should be interpreted in the context of the current first-line ICIs plus anti-VEGF therapy. Evidence on TIGIT-targeting strategies after failure of such regimens remains limited. In LIVERTI, patients were enrolled regardless of prior combinations, although subgroup analyses were not feasible. Resistance may reflect both persistent immune suppression and tumor-intrinsic mechanisms. TIGIT blockade may retain activity in tumors with suppressed but present immune infiltrates, whereas in acquired resistance, additional checkpoint inhibition alone is unlikely to be sufficient.

The use of an Fc-silent antibody may be a critical factor, as emerging evidence suggests that Fc-competent TIGIT antibodies may have unintended immunological consequences that limit efficacy. Moreover, by focusing on a PD-1-refractory population, LIVERTI directly tested a biologically grounded hypothesis that was not addressed in frontline studies such as MORPHEUS-Liver (15). Together, these design elements strengthen the biological interpretability of the trial.

Nevertheless, several limitations must be acknowledged. The modest sample size, lack of randomisation, short follow-up, and limited representation of patients with Child-Pugh B disease constrain the generalizability of the findings. Heterogeneity in prior immunotherapy exposures further complicates interpretation, although it also reflects real-world clinical practice. Overall survival and duration of response remain immature and will be critical endpoints in future studies.

Despite these limitations, LIVERTI provides an essential proof of concept. It demonstrates that targeting TIGIT in combination with PD-1 blockade is feasible, tolerable, and associated with clinically meaningful antitumor activity in a subset of patients with immunotherapy-refractory HCC (11). The trial also raises key questions for the field, including whether TIGIT-based combinations can outperform TKIs in post-ICI settings; whether the benefit is limited to tumours with primary rather than acquired resistance; whether ctDNA can be validated as a standardised early response biomarker; and how TIGIT inhibition should be integrated into broader immunotherapy strategies.

In summary, while the LIVERTI trial does not yet change clinical practice, it provides compelling early evidence that TIGIT-PD-1 dual inhibition may offer a new therapeutic avenue for patients with HCC who have exhausted standard immunotherapy options. It underscores the need for precision immunotherapy approaches tailored to distinct resistance phenotypes. In a disease where post-ICI strategies remain deeply inadequate, even modest response signals—when coupled with favourable toxicity and strong mechanistic rationale—are highly significant. Nevertheless, these findings should be considered hypothesis-generating, and larger randomized phase III studies will be required to confirm the efficacy and safety of PD-1 plus Fc-silent anti-TIGIT antibodies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-1-960/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-1-960/coif). The authors have no conflicts of interest to declare.

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