Role of Interleukin(IL)-6 in NK Activity to Hypoxic-Induced Highly Invasive Hepatocellular Carcinoma (HCC) Cells

Sep 24, 2026

Hypoxia within the tumor microenvironment alters natural killer (NK) cell function against hepatocellular carcinoma (HCC). In cancer cells, hypoxia-inducible factor (HIF) transcription supports adaptation and immune escape, while HIF-1α correlates with pro-inflammatory cytokines. This study links HIF-1α expression in HCC cells with IL-6 presence during HCC–NK interaction. Blocking IL-6 with antibody shifts cytokine production, increasing IL-21, and IL-6 absence enhances cytotoxicity and activating receptor expression (NKG2D, NKp44, NKG2C) toward HIF-1α-expressing HCC, potentially via reduced STAT3 phosphorylation and lowered HIF-1α.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

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Introduction

Pro-inflammatory cytokines in tumor microenvironment and IL-6

NK cell role and tumor microenvironment influences

Hypoxia, HIF-1α, and immune escape mechanisms

J. Microbiol. Biotechnol. 2023. 33(7): 864–874 [https://doi.org/10.4014/jmb.2304.04023](https://doi.org/10.4014/jmb.2304.04023) Received: April 14, 2023 Accepted: June 1, 2023 First published online: June 12, 2023 *Corresponding authors H. H. Lee Phone: +82-2-901-8734 [E-mail: oeo3oeo@gmail.com](E-mail: oeo3oeo@gmail.com)[ ](E-mail: oeo3oeo@gmail.com)H. Cho Phone: +82-2-901-8678 E-mail: hyosun1102@duksung. [ac.kr](ac.kr) Supplementary data for this paper are available on-line only at [http:](http://jmb.or.kr)[//](http://jmb.or.kr)[jmb.or.kr](http://jmb.or.kr). pISSN 1017-7825 eISSN 1738-8872 Copyright © 2023 by the authors. Licensee KMB. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Role of Interleukin(IL)-6 in NK Activity to Hypoxic-Induced Highly Invasive Hepatocellular Carcinoma(HCC) Cells Hwan Hee Lee1,2*, Hyojung Kang3, and Hyosun Cho1,2* 1Department of Pharmacy, Duksung Women’s University, Seoul 01369, Republic of Korea 2Duksung Innovative Drug Center, Duksung Women’s University, Seoul 01369, Republic of Korea 3Vessel-Organ Interaction Research Center, VOICE (MRC), Cancer Research Institute, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea Natural killer (NK) cell dysfunctions against hepatocellular carcinoma (HCC) in a hypoxic environment. Many solid tumors are present in a hypoxic condition, which changes the effector function of various immune cells. The transcription of hypoxic-inducible factors (HIFs) in cancer cells make it possible to adapt to their hypoxic environment and to escape the immune surveillance of NK cells. Recently, the correlation between the transcription of HIF-1α and pro-inflammatory cytokines has been reported. Interleukin (IL)-6 is higher in cancers with a highly invasive ability, and is closely related to the metastasis of cancers. This study showed that the expression of HIF-1α in HCC cells was associated with the presence of IL-6 in the environment of HCC-NK cells. Blocking of IL-6 by antibody in the HCCNK interaction changed the production of several cytokines including TGF-β, IL-1, IL-18 and IL-21 . Interestingly, in a co-culture of HIF-1α-expressed HCC cells and NK cells, blocking of IL-6 increased the production of IL-21 in their supernatants. In addition, the absence of IL-6 significantly enhanced the cytotoxic ability and the expression of the activating receptors (NKG2D, NKp44, and NKG2C) in NK cells to HIF-1α-expressed HCC cells. These effects might be made by the decreased expression of HIF-1α in HCC cells through the inhibited phosphorylation of STAT3. In conclusion, the absence of IL- 6 in the interaction of HIF-1α-expressed HCC cells and NK cells could enhance the antitumor activity of NK cells to HCC cells. Keywords: Natural killer (NK) cell, Hepatocellular carcinoma (HCC), hypoxia, HIF-1α, Interleukin (IL)-6 Introduction Pro-inflammatory cytokines in a tumor microenvironment (TME) are an important factor in the surveillance of tumors by various immune cells [1] . Recent studies have shown that pro-inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 in a tumor microenvironment contribute to the development and metastasis of cancers through the immune escape of cells [2-4]. Of these, IL-6 is known to be a cytokine that leads to chronic inflammation in several cancers [5, 6]. According to a meta-analysis, the level of IL- 6 in the serum of HCC patients was higher than healthy controls [7], and in particular, it is highest in stage III compared to stage I or II [8] . A natural killer (NK) cell is an innate immune lymphocyte that plays an important role in cancer development. NK cells can directly kill cancer cells and help other immune cells indirectly through the production of several cytokines such as IFN-γ [9, 10]. NK cells account for about 55% of hepatic lymphocytes, and are

FAQs

How does hypoxia affect NK cell surveillance of hepatocellular carcinoma?

Hypoxia in the tumor microenvironment changes the effector function of immune cells, including NK cells, contributing to reduced anti-tumor surveillance against HCC.

What relationship does the study propose between HIF-1α and IL-6?

The study shows that HIF-1α expression in HCC cells is associated with the presence of IL-6 in the HCC–NK cell environment.

What happens when IL-6 signaling is blocked in the HCC–NK interaction?

Antibody blocking of IL-6 alters cytokine production and, in co-culture with HIF-1α-expressed HCC cells, increases IL-21. IL-6 absence also enhances NK cytotoxic ability and activating receptor expression (NKG2D, NKp44, NKG2C).

Sep 24, 2026

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