The Oncology of Liver Cancer: Integrating Molecular Insights with Therapeutic Innovation

1. Introduction

Liver cancer is among the most common and deadly malignancies worldwide, ranking as the fourth leading cause of cancer-related mortality [1]. Its incidence continues to rise globally, driven primarily by the increasing prevalence of chronic liver diseases, including viral hepatitis infections and metabolic syndromes [2]. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancer cases, representing a significant clinical and public health challenge due to its aggressive nature and poor prognosis [3]. The complexity of liver cancer arises from the interplay of various etiological factors and molecular alterations, often compounded by late diagnosis and limited therapeutic options. Despite improvements in diagnostic imaging and the introduction of systemic therapies, such as multikinase inhibitors and immunotherapies, survival rates remain dismal for many patients [4,5]. This underscores the critical need for comprehensive understanding of liver cancer biology, early detection methods, and more effective treatment strategies.

2. Cancer and Its General Mechanisms

Cancer is fundamentally a disease of dysregulated cell growth, involving genetic and epigenetic changes that disrupt cell cycle control, apoptosis, angiogenesis, and metastatic capability. In liver cancer, key mutations in genes such as TP53, CTNNB1, and others in the Wnt/β-catenin pathway frequently occur [6,7]. Chronic damage to the liver from viral, metabolic, or toxin-based insults leads to sustained inflammation, fibrosis, and oxidative stress, which together facilitate accumulation of DNA damage and promote a tumor-permissive microenvironment [8,9]. The immune microenvironment in HCC also plays a significant role in enabling immune evasion, with tumor-associated macrophages, regulatory T cells, and checkpoint pathway activation being important mediators [10].

3. Types of Liver Cancer

The majority (≈75-85 %) of primary liver cancers are hepatocellular carcinoma (HCC), arising from hepatocytes in the setting of chronic liver injury [11,12]. HCC is strongly associated with risk factors such as chronic hepatitis B and C infections, alcohol abuse, and increasingly NAFLD/NASH [13,14]. Intrahepatic cholangiocarcinoma (iCCA), accounting for about 10-15 % of primary liver cancers, emerges from bile duct epithelium and often exhibits distinct molecular alterations (e.g. in IDH1/2, FGFR) and worse prognosis due to late presentation [15]. Rare forms include hepatoblastoma in children, and vascular tumors such as angiosarcoma; these are less common but have unique etiologies and biology [16].

Primary liver cancers encompass several histological types with distinct cellular origins and molecular characteristics, as summarized in Table 1.

4. Liver Cancer Etiology: Risk Factors and Pathogenesis

Chronic viral hepatitis (HBV, HCV) remains a dominant etiologic contributor to HCC, mediating ongoing liver inflammation, fibrosis, and promoting genetic instability over years [17,18]. Alcohol use causes direct hepatocellular injury, promotes oxidative stress, and induces fibrotic pathways leading to cirrhosis, another strong risk for HCC [19]. NAFLD and its inflammatory form NASH have become major contributors in many regions, driven by obesity, insulin resistance, and metabolic syndrome [20]. Environmental toxins like aflatoxins also induce mutational signatures (e.g. in TP53) that increase HCC risk [21]. Genetic and epigenetic alterations contribute significantly: besides point mutations, copy number alterations, chromatin remodeling, and methylation changes are evident in many HCC tumors [22,23].

To better understand the etiology of liver cancer, it is important to consider the major risk factors contributing to its development (Table 2).

5. Past and Present Research Status in Liver Cancer

Historically, treatments were dominated by liver resection and transplantation for early disease, and systemic therapies were largely ineffective. For advanced HCC, chemotherapy had little survival benefit [24]. The approval of sorafenib in 2007 marked a milestone: sorafenib showed modest survival benefit (median OS ~10.7 months) in advanced HCC patients over placebo [25]. Later, the REFLECT trial demonstrated that lenvatinib was non-inferior to sorafenib for first-line treatment, with similar overall survival (~13.6 vs. ~12.3 months) and some improvements in progression-free survival (PFS) and response rates [26]. More recently, combinations of therapies have shown superior results: the IMbrave150 trial demonstrated atezolizumab + bevacizumab improved OS (19.2 vs 13.4 months) and PFS compared to sorafenib [27]. The HIMALAYA trial showed that tremelimumab + durvalumab also had better outcomes over sorafenib in first-line advanced settings, with median OS around 16.4 months [28].

Over the past two decades, multiple therapeutic agents have been developed and approved for advanced hepatocellular carcinoma, with their key features outlined in Table 3.

6. Therapeutic Advances in Liver Cancer Treatment

The systemic therapy landscape for HCC has expanded significantly. First-line options now include not just TKIs (sorafenib, lenvatinib) but immunotherapy combinations. Atezolizumab + bevacizumab and tremelimumab + durvalumab are now approved first-line treatments, showing better survival and tolerability compared to sorafenib in appropriate patients [27,28]. For second-line settings, agents such as regorafenib, cabozantinib, ramucirumab (especially in patients with elevated AFP) have demonstrated survival benefits in patients who progressed on sorafenib [29,30]. Immune checkpoint inhibitors (nivolumab, pembrolizumab) have shown durable responses in early trials and are being explored further, though some phase III trials did not meet predefined endpoints for statistical significance [31,32]. Combination therapies (ICI + anti-angiogenic, ICI + TKI, or locoregional + immunotherapy) are increasingly under study to overcome resistance and improve response rates [33,34].

7. Future Directions and Needs

Despite progress, challenges persist. Early detection remains difficult; many patients present with advanced disease. Better biomarkers (molecular, imaging, or liquid biopsy) are needed to identify HCC earlier. Personalized treatment based on genetic, epigenetic, and immunological profiling could help choose therapies that are more likely to succeed in individual patients [35,36]. Also, there is a need to understand and mitigate resistance to immunotherapy and targeted agents; exploring novel combinations, adaptive treatment regimens, and perhaps cell-based therapies like CAR-T or vaccines might be fruitful [37,38]. Finally, improving safety profiles and access to therapies in lower-resource settings will be important for global impact [39,40].

Despite therapeutic advances, several challenges remain in liver cancer management, highlighting the need for focused research priorities (Table 4).

8. Conclusion

Hepatocellular carcinoma (HCC) continues to represent a significant global health burden, despite notable therapeutic advancements in recent years. The advent of immune checkpoint inhibitors and combination therapies has led to a paradigm shift in the management of advanced disease, offering clinical benefit to a subset of patients. Nonetheless, treatment responses remain heterogeneous, with limited durability and a considerable proportion of patients deriving minimal or no benefit from current interventions. These challenges underscore the critical need for continued translational and clinical research aimed at improving early detection, identifying robust predictive and prognostic biomarkers, and developing more efficacious and individualized therapeutic strategies.

Advances in molecular profiling, coupled with an expanding understanding of the tumor immune microenvironment, are poised to inform the rational design of novel combination regimens and overcome mechanisms of therapeutic resistance. Furthermore, ensuring the global accessibility and equitable implementation of emerging diagnostic and treatment modalities is imperative, particularly in regions with high HCC incidence and constrained healthcare infrastructure. Moving forward, a multidisciplinary, precision medicine–oriented approach will be essential to optimize therapeutic outcomes, extend survival, and enhance the quality of life for patients with liver cancer.