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Kwee et al. Hepatoma Res 2022;8:32 https://dx.doi.org/10.20517/2394-5079.2022.58 Page 3 of 4

combined with other biomarkers or patient stratification to address tumor-extrinsic factors such as liver
disease and the liver immune environment discussed earlier.

With regards to imaging as another non-invasive means of obtaining potential multiparametric treatment
response predictors, a recent multi-omics study by Murai et al. that included retrospective analysis of liver
MRI data from 30 patients treated with atezolizumab plus bevacizumab identified intratumoral steatosis
quantified by chemical shift MRI to be associated with significantly improved progression-free survival as
compared to non-steatotic HCC . While compelling as a suggestion that MRI is a potential source of
[14]
immunotherapy biomarkers for HCC, additional independent cohort studies will be needed to substantiate
these results.

In summary, immune checkpoint inhibitor (ICI) regimens are the standard of care for systemic treatment of
advanced, unresectable, or metastatic HCC for the foreseeable future. Because only a minority of HCC
patients are expected to respond to first-line or second-line immunotherapy, biomarkers for identifying
HCC tumors that are immunologically vulnerable are actively being sought. Efforts to develop biomarkers
for predicting immunotherapy response in HCC have met some, although still very limited, success, while
finding a reliable predictor of response has become increasingly challenging due to the growing diversity of
eligible patients and immunotherapy regimens. Informing on the challenges, recent studies clearly
demonstrate that the underlying liver disease and microenvironment can strongly influence HCC immune
avoidance and immunotherapy response. In addition, recent studies have also revealed multiple tumor-
intrinsic mechanisms of immune evasion that could behave differently depending on liver and tumor
microenvironment conditions. Understanding how these factors coalesce to impact immunotherapy
outcomes in advanced HCC will be crucial to finding reliable multiparametric biomarkers of
immunotherapy response and to developing more effective regimens for harnessing or restoring anti-tumor
immunity in HCC.

DECLARATIONS
Authors’ contributions
Each author has made substantial contributions to the conception and writing of this article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by NIH R01CA262460.

Conflicts of interest
All authors declared that there are no conflicts of interest. The contents of this work do not necessarily
reflect the views of The University of Hawaii Cancer Center or The Queen’s Medical Center.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.