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Biomolecules
Special Issues
Tumor Microenvironment, Immunology and Precision Medicine of Liver Cancer
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Tumor Microenvironment, Immunology and Precision Medicine of Liver Cancer

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological Factors".

Deadline for manuscript submissions: 30 November 2025 | Viewed by 2219

Special Issue Editor

Dr. Lynn Jeanette Savic

E-Mail Website
Guest Editor
Department of Radiology, Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, 13353 Berlin, Germany
Interests: liver cancer; tumor microenvironment; locoregional therapies; molecular therapies; translational research

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Despite the variety of available treatments ranging from liver transplantation, resection, or locoregional therapies to systemic treatments, the prognosis of HCC remains unsatisfactory. Unlike other cancers, HCC responds less effectively to immunotherapies due to its complex tumor microenvironment (TME). One postulated factor is its deregulated cellular metabolism, which leads to an immune inhibitory TME characterized by elevated lactate and low pH. Additionally, HCC is frequently found to be hypoxic, which exacerbates metabolic reprogramming and contributes to immune evasion.

Among other immune cells, tumor-associated macrophages (TAMs) can exhibit pro-tumorigenic function when they differentiate towards anti-inflammatory, M2-like subtypes. Given the high plasticity of TAMs, exploring relevant factors in the regulation of macrophage polarization could inform therapeutic decisions and improve the efficacy of immunomodulatory therapies.

In recent years, metabolite alterations, metabolic reprogramming, and potential immunometabolic crosstalk in the TME have attracted increasing attention. Exploring variations in immunity and metabolism in HCC from multiple dimensions and with various approaches may enter the scientific limelight again. This will be beneficial in providing sufficient biological information for the personalized and precise treatment of liver cancer.

Dr. Lynn Jeanette Savic
Guest Editor

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. Biomolecules is an international peer-reviewed open access monthly 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 2700 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

  • hepatocellular carcinoma
  • hypoxia
  • tumor microenvironment
  • immunometabolic crosstalk
  • tumor-associated macrophages

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Published Papers (1 paper)

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Research

15 pages, 2684 KiB  
Article
The Effects of Hypoxia on the Immune–Metabolic Interplay in Liver Cancer
by Yubei He, Han Xu, Yu Liu, Stefan Kempa, Carolina Vechiatto, Robin Schmidt, Emine Yaren Yilmaz, Luisa Heidemann, Jörg Schnorr, Susanne Metzkow, Eyk Schellenberger, Akvile Häckel, Andreas Patzak, Dominik N. Müller and Lynn Jeanette Savic
Biomolecules 2024, 14(8), 1024; https://doi.org/10.3390/biom14081024 - 17 Aug 2024
Cited by 2 | Viewed by 1529
Abstract
M2-like macrophages promote tumor growth and cancer immune evasion. This study used an in vitro model to investigate how hypoxia and tumor metabolism affect macrophage polarization. Liver cancer cells (HepG2 and VX2) and macrophages (THP1) were cultured under hypoxic (0.1% O2) [...] Read more.
M2-like macrophages promote tumor growth and cancer immune evasion. This study used an in vitro model to investigate how hypoxia and tumor metabolism affect macrophage polarization. Liver cancer cells (HepG2 and VX2) and macrophages (THP1) were cultured under hypoxic (0.1% O2) and normoxic (21% O2) conditions with varying glucose levels (2 g/L or 4.5 g/L). Viability assays and extracellular pH (pHe) measurements were conducted over 96 hours. Macrophages were exposed to the tumor-conditioned medium (TCM) from the cancer cells, and polarization was assessed using arginase and nitrite assays. GC-MS-based metabolic profiling quantified TCM meta-bolites and correlated them with M2 polarization. The results showed that pHe in TCMs decreased more under hypoxia than normoxia (p < 0.0001), independent of glucose levels. The arginase assay showed hypoxia significantly induced the M2 polarization of macrophages (control group: p = 0.0120,0.1%VX2-TCM group: p = 0.0149, 0.1%HepG2-TCM group: p < 0.0001, 0.1%VX2-TCMHG group: p = 0.0001, and 0.1%HepG2-TCMHG group: p < 0.0001). TCMs also induced M2 polarization under normoxic conditions, but the strongest M2 polarization occurred when both tumor cells and macrophages were incubated under hypoxia with high glucose levels. Metabolomics revealed that several metabolites, particularly lactate, were correlated with hypoxia and M2 polarization. Under normoxia, elevated 2-amino-butanoic acid (2A-BA) strongly correlated with M2 polarization. These findings suggest that targeting tumor hypoxia could mitigate immune evasion in liver tumors. Lactate drives acidity in hypoxic tumors, while 2A-BA could be a therapeutic target for overcoming immunosuppression in normoxic conditions. Full article
(This article belongs to the Special Issue Tumor Microenvironment, Immunology and Precision Medicine of Liver Cancer)
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