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Livers
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Liver Cancer Heterogeneity in the Era of Single-Cell and Spatial...
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Liver Cancer Heterogeneity in the Era of Single-Cell and Spatial Multiomics

A special issue of Livers (ISSN 2673-4389).

Deadline for manuscript submissions: 30 December 2025 | Viewed by 970

Special Issue Editors

Prof. Dr. Veronika Lukacs-Kornek

E-Mail Website
Guest Editor
Institute of Experimental Immunology, University Bonn, Venusberg Campus 1, 53127 Bonn, Germany
Interests: NASH; immunmodulation; stromal cells; fibroblasts; progenitor cells; HCC; CCA
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ralf Weiskirchen

grade E-Mail Website
Guest Editor
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
Interests: liver disease; fibrosis; biomarker; cytokines; chemokines; translational medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), remain among the most lethal malignancies worldwide, driven in part by their profound heterogeneity at the genetic, cellular, and microenvironmental levels. Traditional bulk profiling approaches have failed to capture the complexity of tumor subtypes, immune landscapes, and stromal interactions that define patient outcomes and therapeutic responses. 

This Special Issue aims to highlight recent advances in resolving liver cancer heterogeneity using high-dimensional technologies, including single-cell RNA sequencing, spatial transcriptomics, multiplexed imaging, and integrated multiomics approaches. We welcome original research papers and comprehensive reviews that explore cellular ecosystems of liver tumors and dissect intercellular signaling networks involved in immune evasion, fibrosis, and therapy resistance.

Prof. Dr. Veronika Lukacs-Kornek
Prof. Dr. Ralf Weiskirchen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Livers is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • HCC
  • CCA
  • liver cancer
  • scRNAseq
  • cellular heterogeneity
  • multiomics approaches

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Published Papers (1 paper)

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Research

17 pages, 1680 KB  
Article
Defining Gene Signature of Tumor-Associated Macrophages in Intrahepatic Cholangiocarcinoma as Target for Immunotherapy Using Single Cell and Bulk RNA Sequencing
by Joshua S. Badshah, Ryan M. Lee, Andrea Reitsma, Marc L. Melcher, Olivia M. Martinez, Sheri M. Krams, Daniel J. Delitto and Varvara A. Kirchner
Livers 2025, 5(4), 53; https://doi.org/10.3390/livers5040053 - 29 Oct 2025
Viewed by 412
Abstract
Background: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis due to late-stage presentation and ineffective systemic therapies. Targeting the tumor microenvironment (TME) in ICC offers new therapeutic possibilities, particularly through tumor-associated macrophages (TAM), which can both promote and inhibit tumor progression. The current study [...] Read more.
Background: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis due to late-stage presentation and ineffective systemic therapies. Targeting the tumor microenvironment (TME) in ICC offers new therapeutic possibilities, particularly through tumor-associated macrophages (TAM), which can both promote and inhibit tumor progression. The current study utilized multi-omics analysis to characterize the gene signature of TAM and explore its therapeutic potential in ICC. Methods: Public GEO datasets provided the basis for analysis. Single-cell RNA sequencing (scRNA-seq) data from five ICCs, three adjacent non-tumorous tissues (ANTs), and four healthy liver samples were examined with Python. To validate scRNA-seq findings, bulk RNA-seq data from 27 ICC and 27 matched ANT samples were assessed using R. Differentially expressed genes were identified with adjusted p-values <0.01 and log2-fold changes >1 or <−1. CIBERSORT pipeline analyzed 22 immune cell subtypes in bulk RNA-seq data. STRING database analyzed the contribution of unique TAM-related genes to networks of protein–protein interactions. Results: TAM population demonstrated phenotypic heterogeneity exhibiting partial gene signatures of inflammatory (MS1) and anti-inflammatory (MS2) macrophages. Unique TAM-associated markers, TREM2, CD9, and PRMT10, showed variable expression within the TAM subpopulation. Bulk RNAseq analysis confirmed the scRNA-seq results, highlighting overexpression of TREM2 and CD9 in most ICC samples versus ANT. Immune cell deconvolution revealed decreased MS1 and MS2 macrophages in ICC, and alterations in adaptive immune profile, suggesting immunotolerant TME. STRING database defined TREM2-LGALS3 axis as a potential target for anti-tumor therapies. Conclusions: TAM represents a unique heterogenous population which is primarily found in ICC TME versus ANT or healthy liver tissue The non-uniform expression of unique gene signature demonstrates additional heterogeneity in the TAM subpopulation and suggests that TREM2+ TAM may be desirable targets for anti-TREM2-LGALS3 immunotherapy. Full article
(This article belongs to the Special Issue Liver Cancer Heterogeneity in the Era of Single-Cell and Spatial Multiomics)
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