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Page 4 of 21 Yang et al. Hepatoma Res 2023;9:48 https://dx.doi.org/10.20517/2394-5079.2023.68

Figure 2. Schematic representation of main therapeutic targets, drugs and signaling pathways for intrahepatic cholangiocarcinoma in
2023. The next generation sequencing is recommended to define the genomic aberration status before systemic therapy for
unresectable or metastatic patients. The altered gene textbox highlighted in green indicates that targeted monotherapy, such as anti-
Fus
Fus
NTRK or anti-RET , is recommended by NCCN in first-line or subsequent-line settings. Accordingly, the gene textbox highlighted in
Fus
red means that targeted therapy alone, such as anti-FGFR2 , anti-IDH1 Mut , anti-HER2 Amp , or anti-BRAF V600E , is recommended only after
front-line systemic therapy. All the targeted agents recommended in the NCCN guideline of BTC (version 2. 2023) are displayed in bold
Fus
for better individualized drug selection. IDH1/2 Mut : isocitrate dehydrogenase-1/2 mutation; FGFR2 : fibroblast growth factor receptor 2
Fus
Fus
fusion; HER2 Amp : human epidermal growth factor 2 amplification; BRAF V600E : BRAF V600E mutation; NTRK : NTRK fusion; RET : RET
fusion.
alterations of FGFR2, BAP1, and IDH1/2 enriched in S4. Compared to subtype S4, S1 presented higher
CA19-9 levels, more metastasis, and worse prognosis. S3 was identified as a characteristic of HBV infection.
Therefore, genetic mutation analysis could help recognize the clinicopathological characteristics and even
prognosis of iCCA.

Genetic mutation-based tumor microenvironment and heterogeneity
ITH is a ubiquitous phenomenon in various types of cancer, as reported by Dentro et al., who showed that
at least one subclonal expansion was found in over 75% of samples across all 38 cancer types except
melanoma . Recently, multi-region sequencing has revealed that iCCA exhibits extremely high ITH at
[21]
[22]
both the genomic and immune microenvironment levels . The differences in gene mutations and copy
number changes exceed 40% between different regions of the same tumor, and more than half of iCCAs
exhibit heterogeneous tumor-infiltrating immunity. iCCA driven by FGFR2 mutations has a lower
neoantigen load and immune infiltration, suggesting that PD1 antibodies may need to be combined with
FGRF2 inhibitors to achieve some efficacy in this situation. In addition, researchers screened the HLA
binding ability and immunogenicity of immune peptides derived from TP53, KRAS, IDH1/2, and BAP1
mutations, and found that the peptide LVVVGADGV derived from KRAS G12D has strong
immunogenicity and may serve as a new target for personalized immunotherapy. Actually, extensive ITH
existed in iCCA at multiple levels, including genomics, transcriptomics, and the immune system. IDH-
mutant iCCA displays increased ITH and colder tumor microenvironment (TME) . Lin et al. employed
[23]
multiomics analysis to categorize 255 iCCA patients into three immune subgroups: IG1 (suppressive in
[24]
25.1%), IG2 (exclusion in 42.7%), and IG3 (activated in 32.2%) . These subgroups exhibited distinct genetic
and molecular characteristics. Subgroup IG1 had the poorest prognosis, with the highest degree of bone
marrow infiltration and abundant KRAS mutations. Evidently, TME and ITH have emerged as pivotal
factors leading to resistance and failure of systemic therapies. Genetic mutation features may help not only
guide targeted therapy but also provide further understanding of the TME and ITH of iCCA.