Table 2.

Biomarkers of response to immune checkpoint inhibitors in advanced HCC.

Response	Refs	Resistance	Ref
Biomarkers of response/resistance in tumor genome
Activation of IFN signaling pathways   4-genes signature   11-genes signature	[60,61]	Copy number alterations (CNA)—loss of heterozygosity of HLA alleles CTNNB1 mutations Activation of WNT/β-catenin pathway	[34,62,63] [64] [64,65]
Biomarkers of response/resistance in tumor tissue
↑ T cell infiltration M1 macrophage polarization ↑ cytotoxicity   INFγ, PRF1, GZMB, TBX21, KLRK1 ↑ Immune cell homing   CXCL9, CXCL10 Antigen presentation—dendritic cells PD-L1 expression in cancer cells and/or immune cells	[34,66] [8,33,34] [34] [34,61] [34] [35,40,41,61]	↑ cancer-associated fibroblast ↑ stromal activation M2 macrophage polarization ↑ CD8+ PD1+ T cells   CCL5, CCL3, GZMK, GZMA, CXCR6 ↑ CD4 Treg cells ↑ Δ42PD-1+ tumor-infiltrating T cells	[34] [33,34] [33,34] [67] [34] [68]
Biomarkers of response/resistance in blood
↑ Baseline CD137 ↓ AFP during treatment	[66] [69]	Antidrug antibodies (ADAs)	[3,70]
Biomarkers of response/resistance associated to the host
Gut microbiota diversity	[71]	Etiology—NASH	[60,67,72]
Clinical markers of immunotherapy activity
Development of immune-related adverse events	[73]

↑ = increase; ↓ = decrease.