In a groundbreaking advancement poised to redefine therapeutic strategies against liver cancer, researchers have unveiled compelling results from the phase 2 LIVERTI trial, exploring the dual blockade of immune checkpoints TIGIT and PD-1. Hepatocellular carcinoma (HCC), notorious for its complex tumor microenvironment and resistance to conventional immunotherapies, has long presented a formidable challenge in oncology. This new study harnesses the synergistic potential of domvanalimab and zimberelimab—two monoclonal antibodies targeting TIGIT and PD-1 respectively—addressing a critical unmet need for patients exhibiting resistance to existing anti-PD-1 therapies.
Hepatocellular carcinoma remains one of the leading causes of cancer-related mortality worldwide, with a dismal prognosis once tumors become refractory to frontline treatments. Current immunotherapies predominantly focus on PD-1 pathway inhibition, yet a significant subset of patients develop adaptive resistance or innate unresponsiveness, necessitating innovative combinatorial approaches. The phase 2 LIVERTI trial strategically investigates the concurrent blockade of PD-1 and TIGIT, a novel immune checkpoint receptor implicated in T cell exhaustion and immune evasion within the tumor microenvironment.
Domvanalimab, an investigational TIGIT-blocking antibody, functions by antagonizing TIGIT receptors on immune effector cells such as cytotoxic T lymphocytes and natural killer (NK) cells. TIGIT engagement typically dampens anti-tumor immune responses, facilitating tumor escape. Zimberelimab, acting as a PD-1 inhibitor, prevents PD-1 from interacting with its ligands PD-L1 and PD-L2, thereby reinvigorating T cell activity. The dual blockade aims to overcome compensatory inhibitory pathways that tumors exploit, restoring a robust immune-mediated cytotoxic assault on hepatocellular carcinoma cells resistant to prior PD-1 monotherapies.
Throughout this multicenter, open-label trial, patients with advanced HCC refractory to frontline PD-1 inhibitors received combined treatment with domvanalimab and zimberelimab. The cohort demonstrated promising clinical benefit, with increased objective response rates compared to historical controls receiving PD-1 inhibition alone. Enhanced progression-free survival was observed, suggesting durable disease control conferred by simultaneous inhibition of TIGIT and PD-1 pathways. Importantly, the safety profile remained manageable, with adverse events consistent with known effects of immune checkpoint blockade, including manageable immune-related toxicities.
Therapeutic resistance in HCC is multifactorial, involving an immunosuppressive tumor microenvironment enriched with regulatory T cells, myeloid-derived suppressor cells, and immunoinhibitory molecules. By targeting TIGIT, domvanalimab disrupts a critical suppressive axis that contributes to T cell exhaustion, thereby unleashing the cytolytic potential of CD8+ T cells and NK cells within the hepatic tumor milieu. PD-1 blockade with zimberelimab simultaneously prevents T cell anergy, effectuating a combinatorial immunomodulatory effect superior to single-agent checkpoint inhibition.
Advanced molecular analyses from patient biopsies underscore this synergy. Post-treatment tumor specimens exhibited elevated infiltration of activated CD8+ T cells expressing granzyme B and interferon-gamma, markers indicative of potent anti-tumor activity. Additionally, TIGIT expression on tumor-infiltrating lymphocytes decreased, corroborating effective receptor occupancy by domvanalimab. Transcriptomic profiling revealed upregulation of inflammatory cytokines and chemokines essential for sustaining an immune-activated state, further validating the mechanistic basis of this dual blockade strategy.
One of the critical revelations from the LIVERTI trial is the indication that TIGIT may serve as a compensatory checkpoint upregulated in response to PD-1 inhibition, representing a resistance mechanism exploited by HCC tumors. By concomitantly targeting both receptors, the trial provides compelling rationale for a new paradigm in immunotherapy where combination regimens are tailored to intercept multiple inhibitory signals within the tumor microenvironment. This approach holds promise for transforming outcomes not only in hepatocellular carcinoma but potentially across other PD-1 refractory malignancies.
The implications of this research transcend clinical efficacy. The LIVERTI trial pioneers a biomarker-driven framework for patient selection and therapeutic monitoring. Dynamic assessment of TIGIT and PD-1 expression levels, alongside immune cell phenotyping, may refine prognostication and optimize personalized treatment strategies. Such precision medicine approaches could maximize therapeutic benefit while minimizing unnecessary exposure and associated toxicities, marking a significant step toward adaptive tumor immunotherapy.
Moreover, this study sparks renewed interest in the biology of TIGIT, a relatively underexplored checkpoint receptor compared to CTLA-4 and PD-1. TIGIT’s role in modulating NK cell function and crosstalk with other immune checkpoints highlights its central position in immune homeostasis and tumor immune escape. Illuminating its pathways fosters drug development pipelines investigating next-generation agents that might synergize with current immunotherapies or serve as stand-alone modalities.
With the burgeoning landscape of immuno-oncology, combinatorial therapies such as domvanalimab plus zimberelimab exemplify strategic innovation aimed at surmounting resistance and enhancing durable clinical responses. The promising results reported in this phase 2 trial set the stage for larger, randomized studies to validate these findings and potentially secure regulatory approval for dual TIGIT/PD-1 blockade in refractory hepatocellular carcinoma. Such advancements could herald a new era in immunotherapy characterized by multipronged checkpoint inhibition tailored to tumor-specific immune landscapes.
In conclusion, the phase 2 LIVERTI trial delivers compelling evidence that targeting both TIGIT and PD-1 pathways using domvanalimab and zimberelimab may overcome resistance barriers inherent in hepatocellular carcinoma refractory to PD-1 monotherapy. This dual checkpoint blockade invigorates anti-tumor immunity, prolongs disease control, and maintains a tolerable safety profile, positioning this regimen as a frontrunner in next-generation immuno-oncology treatment paradigms. As the oncology community anticipates subsequent phase 3 data, these findings imbue hope for improved survival in one of the most intractable cancers.
Future research building upon this trial’s insights will likely entail mechanistic dissection of immune cell subpopulations mediating response, exploration of combinatorial strategies incorporating other immune modulators or targeted agents, and refinement of predictive biomarkers. The potential to effectively ‘reprogram’ the immunosuppressive tumor microenvironment through synergistic checkpoint blockade underscores the transformative promise of precision immunotherapy in combating refractory hepatocellular carcinoma.
In an era defined by immunotherapeutic breakthroughs, the LIVERTI trial underscores the value of rational combination checkpoint blockade to recalibrate anti-tumor immunity. By illuminating the therapeutic potential of targeting TIGIT alongside PD-1, this study propels the field closer to surmounting adaptive resistance mechanisms and achieving sustained remission for patients burdened by aggressive hepato-oncologic disease.
Subject of Research: Dual TIGIT and PD-1 checkpoint blockade therapy in hepatocellular carcinoma resistant to anti-PD-1 treatment
Article Title: Dual TIGIT and PD-1 blockade with domvanalimab plus zimberelimab in hepatocellular carcinoma refractory to anti-PD-1 therapies: the phase 2 LIVERTI trial
Article References:
Hsiehchen, D., Kainthla, R., Kline, H. et al. Dual TIGIT and PD-1 blockade with domvanalimab plus zimberelimab in hepatocellular carcinoma refractory to anti-PD-1 therapies: the phase 2 LIVERTI trial.
Nat Commun 16, 5819 (2025). https://doi.org/10.1038/s41467-025-60757-7
Image Credits: AI Generated
