HCC is a heterogeneous disease, symptoms include increased clotting time, jaundice, encephalopathy, with many bodily processes affected and varying degrees of severity.⁶ Complications with underlying liver cirrhosis make HCC difficult to diagnose. 

HCC is caused by injury to the liver.  Over 90% of patients with HCC have underlying chronic liver disease, with cirrhosis being the major risk factor.⁶ Causes of HCC may be viral: hepatitis B/C viruses (HBV/HCV) and non-viral: chronic alcohol, and non alcoholic steatohepatitis (NASH) the more progressive  form of non-alcoholuc fatty liver disease (NAFLD).⁷ Global prevalence of HBV- and HCV- related HCC has been decreasing due to birth dose vaccination, perinatal antiviral prophylaxis, and antiviral agents, shifting to cases caused by NAFLD.⁸

Localized HCC is asymptomatic for much of its natural history.⁹ Nonspecific symptoms associated with more advanced HCC can include jaundice, anorexia, weight loss, malaise, and upper abdominal pain. Physical signs of HCC can include hepatomegaly and ascites. A multidisciplinary care team of different specialties collaborate to diagnose and develop management plans for patients with HCC. Barcelona Clinic Liver Cancer (BCLC) is an HCC staging system consisting of 5 stages based on tumor burden, liver function, and PS score.¹⁰ Child-Pugh classification system determines the severity of liver dysfunction.¹¹

Initially tyrosine kinase inhibitors such as sorafenib and Lenvatinib (VEGFR1/2) were the only treatment options, then immune checkpoint blockers such as atezolizumab and durvalumab were introduced. HCC has limited biomarker-targeted therapies, with α-fetoprotein (AFP)-targeted treatment by ramucirumab being the most common as AFP is overexpressed in ~69% of cases.^{12, 13} There is no established post-progression treatment after first line in unresectable HCC.

Biomarker segmentation in HCC is early and exploratory as targeted therapies with clearly defined biomarkers are still being investigated. Clinical trials are underway for biomarker targets including a c-Met inhibitor, FGFR4 inhibitor, mTORC1/2 inhibitors, GPC3-targeting antibody, and CAR GPC3 T cell therapy.¹⁴ While checkpoint inhibitors (CPIs) are used to treat HCC patients, less than 20% of patients derive lasting clinical benefit as the majority either do not respond to treatment or develop resistance over time.^15,16 The TGF-β pathway is pivotal in HCC pathogenesis and may hinder PD-(L)1-based immunotherapy by upregulation of PD-1.¹⁵ A GARP-TGF-β1 complex targeting antibody in combination with a CPI would inhibit two immunosuppressive pathways, potentially restoring the immune response and promoting T-cell infiltration into the tumor microenvironment