Tetraspan(in)-mediated immune regulation in hepatocellular carcinoma: Editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8⁺ T cell cytotoxic function in hepatocellular carcinoma”

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Clin Mol Hepatol. 2025;31(2):650-653

Publication date (electronic) : 2025 February 11

doi : https://doi.org/10.3350/cmh.2025.0109

Seo Hee Jin^1,*, Dong Joo Kim^1,*, Jung Weon Lee^,1,2

¹Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea

²Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea

Corresponding author : Jung Weon Lee Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea Tel: +82-2-880-2495, Fax; +82-2-872-1795, E-mail: jwl@snu.ac.kr

*Equally contributed.

Editor: Han Ah Lee, Chung-Ang University College of Medicine, Korea

Received 2025 January 31; Accepted 2025 February 7.

Liver cancer is the sixth most diagnosed cancer, and the number of new cases per year is predicted to increase by 55.0% from 2020 to 2040 [1]. The most prevalent type of liver cancer is hepatocellular carcinoma (HCC), which has a very poor prognosis with a 5-year survival rate of <20% [2]. Various treatment strategies have been intensively explored based on disease stage, but none have significantly improved overall survival in HCC patients [3]. Immunotherapies including immune checkpoint inhibitors (ICIs) have been developed as new or combinatory therapeutic options to treat HCC, but the response rates have been limited, presumably because of low efficacy and variable responses among patients [4]. Therefore, there is a growing need to identify new targets for combination therapies and novel biomarkers to predict ICI responsiveness. In this regard, Zeng et al. [5] provide evidence that transmembrane 4 L six family (TM4SF) member 1 (TM4SF1) is involved in HCC progression and resistance to immunotherapy [5].

Based on an analysis of human HCC tissues and public liver cancer datasets, Zeng et al. show that TM4SF1 can promote HCC progression and is negatively correlated with HCC prognosis. Using in vitro hepatocyte cell lines and in vivo studies with genetically engineered mice, they show that TM4SF1 mediates cell proliferation, and its suppression results in non-secretory senescence, with increases in p16 and p21 cyclin-dependent kinase inhibitors (CKIs) and senescence-associated β-gal–positive cells. TM4SF1 binds to AKT and the molecular chaperone PDPK1. The formation of this triple complex leads to TM4SF1/PDPK1-mediated AKT phosphorylation on Ser473, which in turn reduces p16/p21 and MHC1 levels, resulting in senescence escape and HCC progression. Concomitant induction of PD-L1 via TM4SF1-mediated AKT phosphorylation also leads to evasion of immunosurveillance. Thus, TM4SF1 appears to induce PD-L1 and thereby enable immune evasion during HCC development.

The liver is the largest solid and internal organ and contains massive vascular networks, providing a metabolically and immunologically dynamic environment for tumors. To progress, hepatic tumors need to evade immune cell cytotoxicity and/or render immune cells exhausted. Hepatocyte TM4SF1 negatively affects CD8⁺ T cell cytotoxicity by promoting PD-L1 expression. Immunocompetent mice with Tm4sf1 knockdown show increased CD8⁺ T cell populations with higher numbers of granzyme B⁺ and Ifn-γ⁺ T cells, along with fewer PD-1⁺ T cells for enhanced cytotoxicity. By contrast, TM4SF1 overexpression leads to CD8⁺ T cell exhaustion, with higher PD-1 and TIM-3 expression on T cells and reduced numbers of senescence-associated β-gal–positive cells. Cellular senescence is one of the key mechanisms that inhibit tumor cell growth and promote cancer-associated immune responses [6], and TM4SF1 knockdown appears to reprogram the hepatocyte cell fate from cancerous to senescent. Therapeutic strategies using anti-PD-1 antibody and/or Tm4sf1 knockdown reduce tumor burdens in multiple HCC models in immunodeficient or immunocompetent mice, but only Tm4sf1 knockdown reduces senescent features, whereas anti-PD-1 therapy has no such effect. Thus, targeting TM4SF1 can induce senescence to inhibit HCC progression, while combined therapy synergistically reduces tumor burden with a trend for differentiation of naïve CD8⁺ T cells into effector T cells for enhanced cytotoxicity. Based on these results, the authors claim that targeting TM4SF1 may sensitize HCC to anti-PD-1 immunotherapy (Fig. 1).

Figure 1.

TM4SFs-mediated immune exhaustion in HCC development. TM4SF1 in hepatocytes can bind Akt1 and PDPK1 for AKT activity-mediated suppression of p16 and p21 and for PD-L1 and mHC1 induction, leading to escape from senescence and promote proliferation and tumor formation (part with a gray background). Likewise, other transmembrane 4 L six family members (TM4SFs) may interact with immune checkpoints to render internalization and translocation for either lysosomal degradation or recycling back to hepatocyte surface for immune surveillance or exhaustion. HCC, hepatocellular carcinoma; NK, natural killer.

TM4SF proteins, including TM4SF1, have four transmembrane domains, two extracellular loops, and a cytosolic Nor C-terminus and undergo N-glycosylation and lipid modification, which are important for their roles in various homeostatic and pathological contexts [7,8]. Similar to tetraspanins, the TM4SF proteins include members 1, 4, 5, 18, 19, and 20 [9]. The finding that TM4SF1 can regulate immune activity by affecting the PD-L1/PD-1 axis has many potential implications. Indeed, previous studies suggested that tetraspanins and another TM4SF member, TM4SF5, are involved in immune exhaustion [10,11]. Tetraspanins and TM4SFs form protein-protein complexes with other membrane receptors and cytosolic signaling molecules [12]. Zeng et al. show that TM4SF1 binds and activates AKT and PDPK1 to suppress senescence-associated p16/p21 CKIs and increase PD-L1, a protein associated with immune exhaustion. Similarly, AKT-mediated phosphorylation of CKIs (e.g., p27^Kip1) in TM4SF5-positive hepatocytes leads to p27^Kip1 translocation and stabilization in the cytosol to promote tumor progression [13] rather than growth arrest and senescence. Thus, interactions between hepatocyte TM4SFs and CKIs appear to be involved in cancer progression. Furthermore, TM4SF1-mediated AKT activity increases PD-L1 levels in hepatocytes, suggesting an immune-regulatory role. Many studies have shown that the AKT-mTOR pathway can induce PD-L1 in different types of cancer cells [14]. Similar to TM4SF1, TM4SF5 also binds and regulates different immune checkpoints (e.g., SLAMF7) in the abundant natural killer (NK) cells in the liver [15], although any effects of TM4SF5 on the PD-L1/PD-1 axis remain unreported. Therefore, it is likely that targeting TM4SFs can sensitize HCC to T cell and/or NK cell immunotherapy, providing promising targets for new immunotherapeutic reagents and modalities against HCC.

The most important characteristics of ICs may be their abilities to bind other membrane proteins involved in the regulation of immune activity and to traffic subcellularly for cellular context-based control of spatiotemporal actions, resulting in immunosurveillance or immune exhaustion [16]. Residence of ICs on the surface of hepatocytes may be requisite for hepatocyte engagement and/or trogocytosis with immune cells [17]. CTLA-4 is also trafficked intracellularly upon binding with either dimeric CD80 or monomeric CD86, resulting in lysosomal degradation or recycling to the T cell surface as a result of differential pH sensitivities of the proteins at endosomes [18]. Subcellular translocations of protein complexes (including ICs) can be critical for the immune-regulatory roles of TM4SFs, as suggested in a previous research perspective [10]. Thus, TM4SFs may be able to regulate the level, binding, intracellular location, and/or activity of ICs, thus influencing immunosurveillance or immune exhaustion.

In addition to roles in the development of cancer phenotypes, progression, and chemoresistance [19,20], TM4SF1 in hepatocytes is shown to be involved in CD8⁺ T cell exhaustion, resulting in HCC development, whereas TM4SF1 deficiency and anti-PD-1 therapy promote escape to senescence and blockade of HCC development. Thus, TM4SFs, including TM4SF1, by virtue of their protein-binding and subcellular trafficking, can downregulate T cell or NK cell cytotoxicity. Targeting TM4SFs in addition to current immunotherapy may therefore provide an alternative or combinatory strategy to block HCC development and progression.

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