## 1 Introduction  
Hepatocellular carcinoma is a major global health issue, ranking among the most frequently diagnosed cancers and one of the leading causes of cancer-related mortality [1]. According to the most recent data from the Global Cancer Observatory, the global incidence of primary liver cancer is estimated at 866,136 new cases diagnosed annually. This places liver cancer as the sixth most common malignancy worldwide. Alarmingly, the disease also accounts for approximately 758,725 deaths each year, ranking third among the leading causes of cancer-related mortality. _Hepatocellular carcinoma_, the most prevalent form of primary liver cancer, accounts for the majority of these cases. A pronounced sex disparity is evident in the incidence of liver cancer, with men being disproportionately affected compared to women [2]. Hepatocellular carcinoma typically develops in the setting of chronic liver injury, with cirrhosis serving as a common pathological background across diverse etiologies. Globally,chronic infections with the hepatitis B virus (HBV) and hepatitis C virus (HCV) remain major contributors to HCC, accounting for approximately 21% to 55% of cases. Despite notable progress in reducing the burden of viral hepatitis through vaccination programs and antiviral therapies, HCC continues to represent a significant public health concern. This persistent incidence highlights the growing impact of non-viral risk factors. Long-term alcohol consumption, aflatoxin exposure, obesity, and type 2 diabetes [1] are known to drive hepatocarcinogenesis. From an etiopathogenic perspective, HCC arises gradually in the context of chronic inflammation, progressing through various stages of hepatic transformation--from repeated injury and hepatocyte necrosis to regeneration, fibrosis, cirrhosis, and ultimately, malignant transformation [3]. Metabolically associated steatohepatitisitis, the progressive form of steatotic liver disease, now drives the fastest increase in HCC cases and shifts the disease burden from viral to metabolic causes. Hepatocellular carcinoma often reaches an advanced stage before diagnosis because early development typically lacks symptoms. In its initial phases, the disease progresses silently and remains undetected without dedicated screening programs, delaying early intervention. Early detection can raise the five-year survival rate to over 70%. In contrast, patients with symptomatic, advanced-stage HCC face a much poorer prognosis, with a median survival of only 1 to 1.5 years. This sharp difference highlights the urgent need to implement effective surveillance strategies for high-risk individuals and to develop advanced early diagnostic tools that can detect the disease before symptoms appear [4]. Therapeutic approaches for hepatocellular carcinoma vary significantly depending on the stage of the disease, residual liver function, and specific tumor characteristics. Curative interventions, such as surgical resection, are feasible for fewer than 20% of patients. In eligible cases, other treatment options, including liver transplantation, percutaneous ablation, and radiotherapy, are also considered [5]. The characteristics of the tumor microenvironment (TME) add further complexity to treatment. Although tumor-infiltrating T lymphocytes (TILs) are often present, the TME in HCC is profoundly immunosuppressive. This state results from the recruitment and activation of immunosuppressive cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), all of which contribute to immune evasion. Another defining feature of HCC is its intense angiogenesis, mainly driven by pro-angiogenic factors, especially vascular endothelial growth factor (VEGF) [3]. For many patients, chemotherapy remains a central therapeutic strategy, despite its limited impact on survival and considerable toxicity. However, their clinical benefits remain modest, with a median overall survival of around 3 months.