Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.

(1) Background: Cabozantinib is approved in sorafenib-exposed advanced hepatocellular carcinoma (aHCC). We evaluated the real-life pattern of use, efficacy, and tolerability of cabozantinib in aHCC. (2) Methods: This territory-wide study included consecutive aHCC patients who received cabozantinib between February 2018 and September 2020 in Hong Kong. The objective response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events (AE) were assessed. (3) Results: Overall, 42 patients were included. Approximately 83.3% had Child-Pugh A cirrhosis. About 64.3% received cabozantinib as a single agent, and the remaining 35.7% received cabozantinib as an add-on to immune checkpoint inhibitors (ICIs). For single-agent patients, the median follow-up was 6.7 months. The ORR was 3.7%, DCR was 44.4%, and the median OS was 8.28 months. About 74.1% of patients experienced any AEs with 7.4% having grade ≥3 AEs. Among patients who received prior ICIs (n = 16), the ORR was 6.3%, and the median OS was 8.28 months. An exploratory analysis of patients who received cabozantinib as an add-on to ICIs showed an ORR of 6.7% and a median OS of 15.1 months, with 73.3% having any AE and 13.3% having grade ≥3 AEs. (4) Conclusions: Cabozantinib had good anti-tumor activity, survival benefits, and acceptable tolerability in real-life aHCC patients.

Hepatocellular carcinoma (HCC) remains a major global health burden, and therapeutic resistance continues to limit the benefit from systemic treatment. Despite advances in systemic therapies, including immune checkpoint inhibitor-based combinations, antiangiogenic agents, and multitargeted tyrosine kinase inhibitors for patients with advanced HCC, primary non-response and acquired resistance are common. This review summarizes the mechanisms that underlie resistance to contemporary HCC therapies, including tumour heterogeneity, molecular pathway rewiring and crosstalk, tumour microenvironment and immune escape, epigenetic alterations, epithelial-to-mesenchymal transition, and cancer stem cell expansion. We discuss how these mechanisms limit the efficacy of current doublet and triplet regimens, and why biologically rational combinations do not consistently translate into clinical benefit. Emerging strategies to overcome resistance, including biomarker-enriched trial designs and liquid biopsy are also discussed. A deeper integration of mechanistic insights with translational biomarkers will be essential to improve treatment durability and clinical outcomes for patients with HCC.

Solid-organ transplant (SOT) recipients have an increased risk of malignancies and poor oncological prognosis compared to the general population. A central reason for both is that various factors unique to transplantation coalesce to dampen anti-tumor immunity. These include graft or immunosuppressive therapy-related T-cell dysfunction, microenvironmental changes in grafts due to ischemic/reperfusion injuries peri-transplant and comorbidities such as metabolic syndrome. Both innate and adaptive immunity are heavily implicated in cytotoxicity effected by systemic therapeutic agents, not just immune checkpoint inhibitors (ICIs) but also conventional chemotherapy and targeted therapies. Hence, impaired anti-tumor immunity may also affect the treatment efficacy of these agents. Generally, clinical data for systemic therapies in transplant recipients is constrained to retrospective and heterogenous case reports and series only, with a low level of evidence and significant risk of bias. For ICIs, the efficacy in SOT recipients is relatively well preserved in cutaneous squamous cell carcinomas but seems diminished in other tumor types compared to non-transplant recipients. Data for other agents are limited, but the efficacies of chemotherapy in SOT recipients with colorectal cancer and sorafenib/lenvatinib in LT recipients with recurrent hepatocellular carcinoma seem preserved. Given the prevailing trend of broadening the use of transplantation in patients with cancer, further clinical and translational studies to develop strategies to enhance anti-tumor immunity while ensuring graft preservation are urgently needed.