Table 5.

Advantages and disadvantages of each class of biomarker

	Advantages	Issues
Conventional tumor markers, e.g., AFP, DCP	Measurable in routine clinical practice	Not a specific marker of the immune microenvironment. Influenced by tumor burden
Scoring systems, e.g., CRAFITY score	Measurable in routine clinical practice	Not a specific marker of the immune microenvironment. Limited reports on anti-PD-(L)1 + anti-CTLA4
(m)ALBI	Measurable in routine clinical practice	It is a marker of liver reserve function. Cases with poor liver reserve have a poor prognosis regardless of the treatment chosen
Neutrophil-to-lymphocyte ratio (NLR)	Measurable in routine clinical practice	There are racial differences. It may be influenced by factors other than the tumor
Cytokines	The measurement method is well established. Some of the cytokines are measurable in routine clinical practice	The condition of the background liver; comorbidities and tumor burden may have an impact
Peripheral blood immunoprofiling	It may reflect the systemic immune system	There are hurdles to applying this in daily clinical practice. There are hardly any findings that have been validated in different institutions
Liquid biopsy, especially ctDNA	The measurement techniques are well-established, and there are panels that are already in clinical use	The association between mutations and the efficacy of ICIs remains controversial
Gut microbiome	It is the least invasive	There are racial differences. In the field of HCC, there are few results that have been validated across institutions
Imaging	Measurable in routine clinical practice	The signal intensity in the hepatocyte phase of EOB-MRI is influenced by liver function. Quantitative values such as signal intensity vary depending on the equipment and imaging conditions, making direct application difficult. In cases with multiple lesions, there is the issue of which lesion to use for evaluation

AFP alpha-fetoprotein, DCP Des-gamma-carboxy prothrombin, CRAFITY C-reactive protein and alpha fetoprotein in immunotherapy, (m)ALBI (modified) albumin-bilirubin, NLR neutrophil-to-lymphocyte ratio, EOB-MRI gadoxetic acid-enhanced MRI