TYPE Mini Review

PUBLISHED 11 July 2023

DOI 10.3389/fimmu.2023.1230465

Post-translational modifications
OPEN ACCESS and immune responses in
EDITED BY
Xiangpeng Dai,
Jilin University, China
liver cancer
REVIEWED BY
Xiaoling Zhang, You-Wei Wang †, Jia-Chen Zuo †, Chong Chen*
Jilin University, China
Bo Xu, and Xiao-Hong Li*
Xuzhou Medical University, China
Academy of Medical Engineering and Translational Medicine, Medical College of Tianjin University,
*CORRESPONDENCE Tianjin, China
Xiao-Hong Li
xhli18@[Link]
Chong Chen
calphen_cc_gz@[Link]
Post-translational modification (PTM) refers to the covalent attachment of
†
These authors have contributed equally to
functional groups to protein substrates, resulting in structural and functional
this work
changes. PTMs not only regulate the development and progression of liver
RECEIVED 29 May 2023
ACCEPTED 26 June 2023
cancer, but also play a crucial role in the immune response against cancer.
PUBLISHED 11 July 2023 Cancer immunity encompasses the combined efforts of innate and adaptive
CITATION
immune surveillance against tumor antigens, tumor cells, and tumorigenic
Wang Y-W, Zuo J-C, Chen C and Li X-H microenvironments. Increasing evidence suggests that immunotherapies,
(2023) Post-translational modifications and which harness the immune system’s potential to combat cancer, can
immune responses in liver cancer.
Front. Immunol. 14:1230465. effectively improve cancer patient prognosis and prolong the survival. This
doi: 10.3389/fimmu.2023.1230465 review presents a comprehensive summary of the current understanding of
COPYRIGHT key PTMs such as phosphorylation, ubiquitination, SUMOylation, and
© 2023 Wang, Zuo, Chen and Li. This is an glycosylation in the context of immune cancer surveillance against liver
open-access article distributed under the
terms of the Creative Commons Attribution cancer. Additionally, it highlights potential targets associated with these
License (CC BY). The use, distribution or modifications to enhance the response to immunotherapies in the treatment
reproduction in other forums is permitted,
provided the original author(s) and the
of liver cancer.
copyright owner(s) are credited and that
the original publication in this journal is KEYWORDS
cited, in accordance with accepted
academic practice. No use, distribution or hepatocellular carcinoma, post-translational modifications, immune surveillance,
reproduction is permitted which does not phosphorylation, ubiquitination, SUMOylation, glycosylation
comply with these terms.

Introduction
Liver cancer is one of the most common malignancies worldwide and directly causes
nearly one million deaths each year (1). According to global cancer statistics in 2020, liver
cancer is the sixth most diagnosed cancer and the third most common cause of cancer
death (2). In 2020, about 900,000 people worldwide were diagnosed with liver cancer and
about 800,000 died of liver cancer. It is estimated that the number of liver cancer diagnoses
could reach 1.3 million by the year of 2040 (3). Primary liver cancer mainly includes four
types: hepatoblastoma (HB), hepatocellular carcinoma (HCC), cholangiocarcinoma
(CCA), and combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA)
(4). HCC is the main type of primary liver cancer, accounting for approximately 75% of the

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total number of liver cancer cases worldwide. CCA is the second differentiation and functional specialization (17–21). In patients
most common primary liver cancer, of which intrahepatic with HCC, Th1 cytokines of serum level are often suppressed, while
cholangiocarcinoma (ICC) is a highly heterogeneous primary Th2 cytokines are frequently elevated (22). Interleukin-6 (IL-6), one
epithelial liver cancer (5). While novel therapeutic approaches of the Th2 cytokines, has been observed to exhibit a negative
have demonstrated notable clinical efficacy or promising correlation with overall survival rate and can independently serve
prospects in cancer treatment (6), the current primary approach as a predictive factor for survival. Conversely, increase of Th1
for liver cancer therapy is still surgical intervention. cytokine responses have been linked to favorable immunological
Protein translational modifications (PTMs) are covalent effects on the prognosis of HCC (23). An increase in Th1-related
attachment of functional groups to protein substrates and can cytokines and a decrease in Th2-related cytokines was observed in a
alter the activity, stability, protein interaction, and intracellular study on primary HCC after radiofrequency ablation (RFA)
localization of target proteins (7). These modifications involve treatment (22). Th17 cells, a specific subset of T-helper cells, play
addition of chemical groups (methylation, acetylation, a pivotal role in immune responses through the production of IL-17
phosphorylation, etc.), addition of polypeptide chains (24, 25). IL-17 acts on HCC cells and triggers the activation of AKT
(ubiquitination, SUMOylation, etc.), amino acid modification (protein kinase B) through phosphorylation. This activation leads to
(racemization, citrullination, etc.), and addition of complex the production of IL-6 by HCC cells (26). In patients with HCC,
molecules (palmitoylation, oxidation, glycosylation, etc.) (8, 9). there is an elevated presence of Th17 cells compared to healthy
PTMs, whether direct or indirect, have a significant impact on the individuals, and as the severity of HCC malignancy worsens, the
immunogenicity of cancer cells, thereby affecting their recognition levels of Th17 cells further escalate (27).
and susceptibility to immune system. Furthermore, these Macrophages are the main effector cells in chronic
modifications also play a crucial role in shaping the response of inflammation, a known driver of carcinogenesis (28). Serine/
various immune cells, influencing their interactions with liver threonine-protein kinase 4 (STK4) was considered as a pivotal
tumor cells within the microenvironment. PTMs exert a tumor suppressor gene in HCC. Notably, signific ant
significant influence on the initiation, progression, immune downregulation of STK4 expression observed in macrophages
evasion, and immunotherapy of cancers. By investigating PTMs, isolated from HCC patients. This decrease in STK4 expression
we can gain valuable insights into the mechanisms governing shows a strong inverse correlation with the levels of IL-1 receptor-
cancer-immune cell interactions and potentially develop novel associated kinase 1 (IRAK1). Through its interaction with IRAK1
strategies to enhance anti-cancer immune responses. and subsequent phosphorylating it, STK4 exerts inhibitory effects
Acetylation and methylation have received extensive attention on the secretion of proinflammatory cytokines, including IL-6, IL-
in previous reviews (10, 11). In this review, our primary focus will 1b, and tumor necrosis factor-a (TNF-a), particularly following the
be the profound influence of phosphorylation, ubiquitination, activation of Toll-like receptor 4/9 (TLR4/9). This implies that the
glycosylation, and SUMOylation on liver cancers, with a regulatory mechanism mediated by STK4 attenuates the chronic
particular emphasis on their immunological significance. inflammatory response and significantly reduces the probability of
HCC development (29).
Macrophages can be categorized into two subpopulation based
Phosphorylation on their distinct functions: M1 macrophages, which promote
inflammatory responses, and M2 macrophages, which support
Phosphorylation, a highly conserved type of PTM (12), tissue repair and cell proliferation (30). In liver cancers,
primarily targets serine, threonine, or tyrosine residues, and macrophages tend to exhibit excessive M2-like polarization,
involves a reversible reaction mediated by protein kinases and thereby suppressing immune responses against cancer cells.
protein phosphatase (13). This essential modification plays a Re c en t fin dings highlig ht the importan ce of protein
pivotal role in numerous biological processes, including protein phosphorylation in the cancer microenvironment for macrophage
interactions, stability, signal transduction, transcriptional polarization (31). Sirtuin 1 (SIRT1) has been shown to enhance the
regulation, and intracellular localization (14). infiltration of M1-like macrophages and inhibit HCC metastasis.
T cells play a central role in the immune system and tumor This effect is mediated by SIRT1’s ability to enhance nuclear factor
immune response. Some immunotherapies that target T cells, such kappa-B (NF-kB) activation and promote the phosphorylation of
as CAR (Chimeric Antibody Receptor)-T cell therapy and p65, IkB, and IkB kinase (IKK) (22). Zinc finger protein 64
checkpoint inhibitors (15, 16), have shown promising results in (ZFP64), a gene upregulated in HCC patients with unfavorable
cancer immunotherapy. T-cell development, differentiation, and prognosis in anti-PD1 treatment, undergoes direct phosphorylation
activation are intricately regulated by phosphorylation events which at S226 by protein kinase Ca (PKCa), leading to its nuclear
target various transcription factors. These phosphorylation events translocation and the transcriptional activation of macrophage
play a critical role in dictating T cell fates and functions. The colony-stimulating factor (CSF1). CSF1 derived from HCC cells
phosphorylation of specific transcription factors, such as signal further promotes macrophage polarization towards M2 phenotype.
transducer and activator of transcription 1 (STAT1) in Th1 cells, NK (natural killer) cells earned their name due to their
STAT6 in Th2 cells, and STAT3 in Th17 cells, contributes to their remarkable ability to “naturally” eliminate cancer cells without

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the need for prior sensitization, and without being restricted by the IL-2, IL-15, and IL-21 are members of the common gamma
major histocompatibility complex (MHC) (32). Upon entering the chain receptor family cytokines. While they share numerous
tumor microenvironment (TME) or encountering cancer cells, NK similarities, these cytokines also show distinct functions within
cells can eliminate cancer cells through self-destruction NK cells. IL-15 is primarily involved in promoting NK cell
mechanisms (perforin/granzyme mediated) or +antibody- maturation, whereas IL-2 enhances NK cell cytotoxicity (32). IL-
dependent cell-mediated cytotoxicity (ADCC) mechanism (33). In 21 facilitates NK cell proliferation without causing telomere
contrast to the NK cells found in peripheral blood, the liver harbors shortening (46). However, the mechanisms underlying the
two distinct types of NK cells: one shares similarities with discriminatory capacity of NK cells among these closely related
circulating NK cells (cNK cells), while the other primarily resides cytokines, despite their shared receptors, have not been fully
within liver tissue (trNK cells) (34). Despite various pathways easily elucidated. IL-15 serves as a critical regulator in the development
active NK cell cytotoxicity, the killing capacity of NK cells can also and maturation of NK cells (47), and it has demonstrated the ability
be easily inhibited, especially within the TME of HCC. The PI3K/ to restore NK cell dysfunction that is impaired by HCC (48).
AKT/mTOR (phosphoinositide 3-kinase, protein kinase B, and Ubiquitination and deubiquitination processes also play vital roles
mammalian target of rapamycin) signaling pathway plays a during IL-15-mediated NK cell maturation. Similar to IL-2, IL-15
crucial role in the development of HCC and the immune binds to its receptor trigger not only phosphorylation, but also
response of NK cells against HCC. Aberrant activation of the ubiquitination of AKT. Otub1, a deubiquitinases enzyme, is
PI3K/AKT/mTOR pathway confers HCC cells with enhanced involved in inhibiting the ubiquitination of AKT. This negative
metabolic capacity, promoting their proliferation and metastasis regulation exerted by Otub1 serves as a checkpoint mechanism,
(35). The development and cytotoxic capability of NK cells also influencing the function of NK cells (49). IL-2 and IL-15 share two
heavily rely on the activation of the PI3K/AKT/mTOR signaling identical chains in their receptors, and their downstream effects in
pathway (36). PI3K consists of a catalytic subunit, p100, and a NK cells are highly similar. However, Otub1 has minimal impact on
regulatory adapter subunit, p85. The p85 subunit is responsible for the activation of AKT by IL-2. Investigating the differential
linking p100 to activated receptor tyrosine kinases (RTKs), thereby ubiquitination patterns of downstream molecules may provide
activating PI3K and initiating the PI3K/AKT/mTOR signaling new insights and potential avenues for fully understanding the
pathway (37). Tim-3 is one of the checkpoint molecules expressed function and signal transduction mechanism of these common
on the surface of NK cells. Its expression levels are significantly gamma chain cytokines.
elevated in HCC. Bind with phosphatidylserine induces Although the application of CAR-T cell therapy in liver cancer
phosphorylation of Tim-3, which further interferes with PI3K/ is still in its early stages, it holds tremendous promise for future
AKT/mTOR pathway in NK cells. By competitively binding to advancements. A major hurdle in the effectiveness of CAR-T cell
p85, phosphorylated Tim-3 reduces the opportunity for PI3K p110 therapy lies in the rapid ubiquitination and subsequent degradation
to bind with p85 and leads to decreased activity of the downstream of CAR upon interaction with tumor antigens. This phenomenon
AKT/mTOR pathway, thereby suppressing the activity of liver NK presents a significant challenge in maintaining the sustained efficacy
cells, including cNK and trNK (38). of CAR-T cell therapy. Fortunately, recent studies have shown that
by introducing specific mutations that target the amino acid
residues involved in CAR ubiquitination, the long-term killing
Ubiquitination and SUMOylation capacity of CAR-T cells can be significantly improved (50).
Ubiquitination is also linked to other protein or gene regulatory
Ubiquitination is a posttranslational modification wherein mechanisms. For instance, in a study focusing on Treg cells in HCC,
ubiquitin molecules are covalently attached to target proteins it was observed that the expression level of long noncoding RNA
(39). This process relies on the coordinated action of three key lnc-EGFR (Epidermal Growth Factor Receptor) was elevated,
adaptor proteins: ubiquitin activating enzyme (E1), ubiquitin showing a positive correlation with tumor size and EGFR/
conjugating enzyme (E2), and ubiquitin ligase (E3) (40). The forkhead box protein 3 (Foxp3) expression levels. By directly
canonical ubiquitination pathway involves the attachment of binding to EGFR protein, lnc-EGFR preventing its ubiquitination
ubiquitin lysine amino acids (Ub) to glycine residues located at and subsequently stabilizing EGFR, thereby enhancing Treg
the C-terminus of target proteins, while the atypical pathways function and promoting the progression of HCC (51).
involve the conjugation of ubiquitin to cysteine, serine, and SUMO (or SUMOylation), which stands for Small Ubiquitin-
threonine residues on target proteins (41). Ubiquitination can like Modifier, is a protein modification process that commonly
facilitate various downstream responses, including degradation, targets lysine residues, involving the attachment of small regulatory
alterations in activity, changes in subcellular localization, or peptides of approximately 11 KDa. Like ubiquitin, this post-
modulation of protein-protein interactions (42–44). Modulating translational modification regulates various biological processes
ubiquitin levels has been shown to have a profound impact on T cell such as cell division, DNA replication/repair, signal transduction,
activation and can effectively enhance antitumor responses, as and cell metabolism (52). HCC-derived exosomes play a significant
indicated by reference (45). Here, we will shift our focus towards role in remodeling the TME and promoting HCC progression (53).
the impact of ubiquitination on other immune cells. One key factor involved in this process is the pyruvate kinase M2

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isoform (PKM2) found within these exosomes (54, 55). HCC- translational glycosylation is a critical step in regulating IL-12
derived e xosomal PKM2 not only induces metabolic secretion (64). Through molecular biology techniques, mutations
reprogramming in monocytes but also triggers the in the N-glycosylation site (N220) of the p40 subunit, a component
phosphorylation of nuclear STAT3. This phosphorylation leads to of the Th1 cytokine IL-12, have been shown to reduce the secretion
the up-regulation of differentiation-associated transcription factors, of free p40. However, these mutations have minimal impact on IL-
promoting M2-like macrophage differentiation. The SUMOylation 12 secretion. As a result, they significantly enhance long-term CD8+
of PKM2 is responsible for its plasma membrane targeting and T cell responses and provide protection against tumor attacks.
subsequent excretion through interaction with arrestin-domain- These mutations can be utilized as adjuvants to generate long-
containing protein 1 (ARRDC1). Additionally, the cytokines and term memory T cells (65).
chemokines secreted by macrophages further reinforce the Keratinocyte-associated protein 2 (KRTCAP2) is a critical
association between PKM2 and ARRDC1 in HCC. This protein involved in N-glycosylation processes, which play a
reinforcement occurs through a CCL1-CCR8 axis-dependent fundamental role in the modification of proteins with complex
mechanism, ultimately promoting the excretion of PKM2 from sugar molecules in various cellular contexts. In HCC, there is a
HCC cells. Consequently, a feed-forward regulatory loop is formed, notable upregulation of KRTCAP2 expression, highlighting its
contributing to tumorigenesis (55). potential significance in HCC pathogenesis and progression.
Interestingly, high levels of KRTCAP2 are associated with a
decreased infiltration of CD8+ T cells and CD68+ macrophages,
Glycosylation both in the tumor region and the surrounding stroma. Furthermore,
the expression level of KRTCAP2 shows a negative correlation with
Glycosylation is a form of co-translational and post- the expression of PD-L1 in HCC (66). The interaction between PD-
translational modification that involves the attachment of glycans 1 and PD-L1 serves as a critical immune checkpoint and has gained
to proteins. It is primarily categorized into two types: N-chain significant recognition as a prominent target for cancer
glycosylation, where the glycan is linked to asparagine residues, and immunotherapy. Elucidating the precise role of KRTCAP2 in the
O-chain glycosylation, where the glycan is attached to oxygen atoms modulation of the TME holds considerable scientific significance
on the hydroxyl groups of serine or threonine amino acid residues and translational potential for overcoming immunosuppression
within protein (56). Many tumor-associated antigens related to in HCC.
HCC are highly glycosylated proteins, and their glycosylation
profiles undergo significant changes in HCC patients (56).
Aberrant glycosylation not only promotes the proliferation and Summary and discussion
metastasis of HCC but also plays an important role in immune
recognition and immune escape. Liver cancer is a common malignant tumor, which poses a great
Abnormally expressed alpha-fetoprotein (AFP) in HCC has an threat to human health and life. Protein posttranslational
inhibitory effect on tumor immune surveillance. It has long been modification and immune response play an important role in the
observed that AFP in HCC undergoes different glycosylation development of liver cancer, the immune surveillance against liver
compared with normal AFP (57). Tumor-derived AFP exhibits cancer, and the treatment of patients with liver cancer. Figure 1
stronger immunosuppressive effects, characterized by lower summarized a mechanism by which PTM contributed in cytokine
dendritic cell maturation and decreased T cell activation (58). mediated cancer immune surveillance. Numerous studies have
Recent studies using single-cell metabolic profiling and single-cell shown promising therapeutic potential in targeting PTM for liver
energetic metabolism by profiling translation inhibition techniques cancer treatment. STT3A is a endoplasmic reticulum-associated N-
have found that HCC-derived AFP binds significantly more glycosyltransferase, which glycosylates PD-L1 and maintain its
polyunsaturated fatty acids than normal AFP. Phagocytosis of stability (67). One notable finding is that spermine, a natural
HCC-derived AFP reduced fatty acid uptake by dendritic cells, polyamine compound, can activate b-catenin, a protein involved
increased glucose uptake and metabolism, decreased expression of in cell adhesion and signaling pathways. Activation of b-catenin
co-stimulatory molecules, and increased expression of immune leads to the transcriptional expression of PD-L1 and N-
checkpoint molecules such as PD-L1. These mechanisms help the glycosyltransferase STT3A (68). Targeting STT3A might be a
tumor evade T cell mediated immune surveillance (59). potential strategy for improving the response to checkpoint
IL-12 is a cytokine of significant importance in promoting T cell inhibitors in HCC patients.
differentiation and IFN-g production. IL-12 not only activates CD8+ In the treatment of HCC, certain drugs have been observed to
T cells and NK cells in HCC tumors (60) but also enhances the induce alterations in glycosylation. Sorafenib, for instance, has
cytotoxicity of Glypican-3-targeting CAR-T cells (61). IL-12 (p70) been identified as capable of modifying the glycosylation patterns
is composed of two subunits, p30 and p40. The free p40 subunit can of multiple proteins in HCC. Further research is needed to
act as a negative regulator by blocking the binding of IL-12 to its determine whether these changes can be targeted to enhance
receptor, thereby inhibiting the biological activity of IL-12 (62). The the efficacy of this HCC therapeutic drugs (69). Additionally,
IL-12 cytokine and its family members are glycoproteins (63). Post- researchers are exploring novel approaches that focus on the

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FIGURE 1
Cytokine relevant post-translational modification and immune surveillance. IL-15 active PI3K/AKT/mTORC1 pathway through phosphorylation and
ubiquitination. Phosphorylated Tim-3 competitively inhibits this pathway, while Otub1 downregulates it by deubiquitination. Glycosylation of p40
increases the secretion of free p40, leading to the attenuation of IL-12 signaling.

TABLE 1 Examples of PTM targeting immunotherapy studies for HCC.

Immune
Drug PTM Treatment rationale References
cells
TLR3 agonist with
DCs Phosphorylation Decreasing phosphorylation of AKT, MEK1/2, ERK1/2 and played an anti-HCC role. (71)
sorafenib

Inhibiting tumor growth in vivo by blocking the VEGF-NRP-1 axis through

MY1340 DCs Phosphorylation (72)
phosphorylation of p65 NF-kB and ERK1/2.

Macrophages, Inducing ubiquitination-mediated mortalin degradation to inhibit angiogenesis and

Caffeic acid (C9H8O4) Ubiquitination (73)
T cells reverse sorafenib resistance.

Promoting the ubiquitin degradation of PD-L1 in HBx-induced HCC and showing an

DMC CD8+T cells Ubiquitination (74)
anti-hepatoma function.

Targeting MUC1
CAR-T cells Glycosylation Targeting MUC1 aberrant O-glycosylation can control HCC growth. (75)
Glycosylation

MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase; HCC, hepatocellular carcinoma; VEGF, vascular endothelial growth factor; NRP,
neuropilin; NF-kB, nuclear factor kappa-B; DMC, 2,5-dimethylcelecoxib; HBx, hepatitis B virus X; MUC1, Mucin1.

aberrant glycosylation sites of tumor-associated antigens in HCC. Funding

These strategies involve the utilization of antibodies or antigen
specific T cells with the aim of converting specific tumor- This work was supported by the National Key Research and
associated antigens into tumor-specific antigens. Although Development Plan of China (2021YFF1200800), the National
these studies are still in their early stages, promising preclinical Nature Scientific Foundation of China (82171861, 81971782).
prospects have already emerged (70). Some studies aiming to
establish PTM based immunotherapy strategies against HCC
were listed in Table 1. Conflict of interest
In this review, we summarized the current knowledge of post-
translational modification of protein in liver cancer cells, tumor The authors declare that the research was conducted in the
infiltrated immune cells, and the microenvironment of liver cancer. absence of any commercial or financial relationships that could be
Unraveling the intricate network of post-translational modifications construed as a potential conflict of interest.
in liver cancer holds great promise for advancing our understanding
of this disease and undoubtedly contributes to the development of
more effective and personalized treatments.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
Author contributions organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
Y-WW and J-CZ contributed equally to this study. All authors claim that may be made by its manufacturer, is not guaranteed or
contributed to the article and approved the submitted version. endorsed by the publisher.

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Wang et al. 10.3389/fimmu.2023.1230465

References
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer 24. Sahu U, Khare P. Role of interleukin-17 in human papillomavirus infection and
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 associated malignancies. Microb Pathog (2021) 161(Pt B):105294. doi: 10.1016/
cancers in 185 countries. CA Cancer J Clin (2018) 68(6):394–424. doi: 10.3322/ [Link].2021.105294
caac.21492 25. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev
2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Immunol (2009) 27:485–517. doi: 10.1146/[Link].021908.132710
cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 26. Gu FM, Li QL, Gao Q, Jiang JH, Zhu K, Huang XY, et al. IL-17 induces AKT-
36 cancers in 185 countries. CA Cancer J Clin (2021) 71(3):209–49. doi: 10.3322/ dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular
caac.21660 carcinoma. Mol cancer (2011) 10:150. doi: 10.1186/1476-4598-10-150
3. Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, et al. Global burden 27. Lan YT, Fan XP, Fan YC, Zhao J, Wang K. Change in the Treg/Th17 cell
of primary liver cancer in 2020 and predictions to 2040. J Hepatol (2022) 77(6):1598– imbalance in hepatocellular carcinoma patients and its clinical value. Med (Baltimore)
606. doi: 10.1016/[Link].2022.08.021 (2017) 96(32):e7704. doi: 10.1097/MD.0000000000007704
4. Liang N, Yang T, Huang Q, Yu P, Liu C, Chen L, et al. Mechanism of cancer 28. Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-
stemness maintenance in human liver cancer. Cell Death Dis (2022) 13(4):394. doi: environment in tumor progression: the role of tumor-associated macrophages. Crit Rev
10.1038/s41419-022-04848-z Oncol Hematol (2008) 66(1):1–9. doi: 10.1016/[Link].2007.07.004
5. Ma J, Li J, Jin C, Yang J, Zheng C, Chen K, et al. Association of gut microbiome 29. Li W, Xiao J, Zhou X, Xu M, Hu C, Xu X, et al. STK4 regulates TLR pathways
and primary liver cancer: a two-sample Mendelian randomization and case-control and protects against chronic inflammation-related hepatocellular carcinoma. J Clin
study. Liver Int (2023) 43(1):221–33. doi: 10.1111/liv.15466 Invest (2015) 125(11):4239–54. doi: 10.1172/JCI81203
6. Han J, Yang W, Li Y, Li J, Jiang F, Xie J, et al. Combining doxorubicin-conjugated 30. Murray PJ. Macrophage polarization. Annu Rev Physiol (2017) 79:541–66. doi:
polymeric nanoparticles and 5-aminolevulinic acid for enhancing radiotherapy against 10.1146/annurev-physiol-022516-034339
lung cancer. Bioconjug Chem (2022) 33(4):654–65. doi: 10.1021/[Link].2c00066
31. Li Y, Cai L, Wang H, Wu P, Gu W, Chen Y, et al. Pleiotropic regulation of
7. Zhou L, Ng DS, Yam JC, Chen LJ, Tham CC, Pang CP, et al. Post-translational macrophage polarization and tumorigenesis by formyl peptide receptor-2. Oncogene
modifications on the retinoblastoma protein. J Biomed Sci (2022) 29(1):33. doi: (2011) 30(36):3887–99. doi: 10.1038/onc.2011.112
10.1186/s12929-022-00818-x
32. Caligiuri MA. Human natural killer cells. Blood (2008) 112(3):461–9. doi:
8. Gupta R, Sahu M, Srivastava D, Tiwari S, Ambasta RK, Kumar P. Post- 10.1182/blood-2007-09-077438
translational modifications: regulators of neurodegenerative proteinopathies. Ageing
Res Rev (2021) 68:101336. doi: 10.1016/[Link].2021.101336 33. Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy.
Nat Rev Clin Oncol (2021) 18(2):85–100. doi: 10.1038/s41571-020-0426-7
9. Xu H, Wang Y, Lin S, Deng W, Peng D, Cui Q, et al. PTMD: a database of human
disease-associated post-translational modifications. Genomics Proteomics Bioinf (2018) 34. Peng H, Tian Z. Re-examining the origin and function of liver-resident NK cells.
16(4):244–51. doi: 10.1016/[Link].2018.06.004 Trends Immunol (2015) 36(5):293–9. doi: 10.1016/[Link].2015.03.006
10. Ding P, Ma Z, Liu D, Pan M, Li H, Feng Y, et al. Lysine Acetylation/ 35. Tian LY, Smit DJ, Jucker M. The role of PI3K/AKT/mTOR signaling in
Deacetylation modification of immune-related molecules in cancer immunotherapy. hepatocellular carcinoma metabolism. Int J Mol Sci (2023) 24(3):2652. doi: 10.3390/
Front Immunol (2022) 13:865975. doi: 10.3389/fimmu.2022.865975 ijms24032652
11. Jarrold J, Davies CC. PRMTs and arginine methylation: cancer’s best-kept 36. Ali AK, Nandagopal N, Lee SH. IL-15-PI3K-AKT-mTOR: a critical pathway in
secret? Trends Mol Med (2019) 25(11):993–1009. doi: 10.1016/[Link].2019.05.007 the life journey of natural killer cells. Front Immunol (2015) 6:355. doi: 10.3389/
fimmu.2015.00355
12. Kumar R, Mehta D, Mishra N, Nayak D, Sunil S. Role of host-mediated post-
translational modifications (PTMs) in RNA virus pathogenesis. Int J Mol Sci (2020) 22 37. Cantrell DA. Phosphoinositide 3-kinase signalling pathways. J Cell Sci (2001)
(1):323. doi: 10.3390/ijms22010323 114(Pt 8):1439–45. doi: 10.1242/jcs.114.8.1439
13. Ardito F, Giuliani M, Perrone D, Troiano G, Lo Muzio L. The crucial role of 38. Tan S, Xu Y, Wang Z, Wang T, Du X, Song X, et al. Tim-3 hampers tumor
protein phosphorylation in cell signaling and its use as targeted therapy (Review). Int J surveillance of liver-resident and conventional NK cells by disrupting PI3K signaling.
Mol Med (2017) 40(2):271–80. doi: 10.3892/ijmm.2017.3036 Cancer Res (2020) 80(5):1130–42. doi: 10.1158/[Link]-19-2332
14. Keck F, Ataey P, Amaya M, Bailey C, Narayanan A. Phosphorylation of single 39. Ciechanover A, Hod Y, Hershko A. A heat-stable polypeptide component of an
stranded RNA virus proteins and potential for novel therapeutic strategies. Viruses ATP-dependent proteolytic system from reticulocytes. 1978. Biochem Biophys Res
(2015) 7(10):5257–73. doi: 10.3390/v7102872 Commun (2012) 425(3):565–70. doi: 10.1016/[Link].2012.08.025
15. Marofi F, Rahman HS, Achmad MH, Sergeevna KN, Suksatan W, Abdelbasset 40. Dong Y, Yang C, Pan F. Post-translational regulations of Foxp3 in treg cells and
WK, et al. A deep insight into CAR-T cell therapy in non-Hodgkin lymphoma: their therapeutic applications. Front Immunol (2021) 12:626172. doi: 10.3389/
application, opportunities, and future directions. Front Immunol (2021) 12:681984. doi: fimmu.2021.626172
10.3389/fimmu.2021.681984 41. Vosper JM, McDowell GS, Hindley CJ, Fiore-Heriche CS, Kucerova R, Horan I,
16. Grosser R, Cherkassky L, Chintala N, Adusumilli PS. Combination et al. Ubiquitylation on canonical and non-canonical sites targets the transcription
immunotherapy with CAR T cells and checkpoint blockade for the treatment of factor neurogenin for ubiquitin-mediated proteolysis. J Biol Chem (2009) 284
solid tumors. Cancer Cell (2019) 36(5):471–82. doi: 10.1016/[Link].2019.09.006 (23):15458–68. doi: 10.1074/jbc.M809366200
17. Ai K, Li K, Jiao X, Zhang Y, Li J, Zhang Q, et al. IL-2-mTORC1 signaling 42. Culver JA, Li X, Jordan M, Mariappan M. A second chance for protein targeting/
coordinates the STAT1/T-bet axis to ensure Th1 cell differentiation and anti-bacterial folding: ubiquitination and deubiquitination of nascent proteins. Bioessays (2022) 44
immune response in fish. PloS Pathog (2022) 18(10):e1010913. doi: 10.1371/ (6):e2200014. doi: 10.1002/bies.202200014
[Link].1010913 43. Cockram PE, Kist M, Prakash S, Chen SH, Wertz IE, Vucic D. Ubiquitination in
18. Lei D, Liu L, Xie S, Ji H, Guo Y, Ma T, et al. Dexmedetomidine directs T helper the regulation of inflammatory cell death and cancer. Cell Death Differ (2021) 28
cells toward Th1 cell differentiation via the STAT1-T-Bet pathway. BioMed Res Int (2):591–605. doi: 10.1038/s41418-020-00708-5
(2021) 2021:3725316. doi: 10.1155/2021/3725316 44. Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu Rev Biochem
19. Han C, Sheng Y, Wang J, Zhou X, Li W, Zhang C, et al. LncRNA PSCK6-AS1- (2009) 78:399–434. doi: 10.1146/[Link].78.101807.093809
HIPK2 promotes Th1 differentiation via STAT1 phosphorylation to regulate colitis- 45. Gavali S, Liu J, Li X, Paolino M. Ubiquitination in T-cell activation and
related mucosal barrier damage. Int immunopharmacol (2023) 117:109992. doi: checkpoint inhibition: new avenues for targeted cancer immunotherapy. Int J Mol
10.1016/[Link].2023.109992 Sci (2021) 22(19):10800. doi: 10.3390/ijms221910800
20. Huang S, Dong D, Zhang Y, Chen Z, Geng J, Zhao Y. NEAT1 regulates Th2 cell 46. Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson
development by targeting STAT6 for degradation. Cell Cycle (2019) 18(3):312–9. doi: JL, et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human
10.1080/15384101.2018.1562285 natural killer cells. PloS One (2012) 7(1):e30264. doi: 10.1371/[Link].0030264
21. Zhu J, Guo L, Watson CJ, Hu-Li J, Paul WE. Stat6 is necessary and sufficient for 47. Ma S, Caligiuri MA, Yu J. Harnessing IL-15 signaling to potentiate NK cell-
IL-4’s role in Th2 differentiation and cell expansion. J Immunol (2001) 166(12):7276– mediated cancer immunotherapy. Trends Immunol (2022) 43(10):833–47. doi: 10.1016/
81. doi: 10.4049/jimmunol.166.12.7276 [Link].2022.08.004
22. Zhou B, Yang Y, Li C. SIRT1 inhibits hepatocellular carcinoma metastasis by 48. Easom NJW, Stegmann KA, Swadling L, Pallett LJ, Burton AR, Odera D, et al.
promoting M1 macrophage polarization via NF-kB pathway. Onco Targets Ther (2019) IL-15 overcomes hepatocellular carcinoma-induced NK cell dysfunction. Front
12:2519–29. doi: 10.2147/OTT.S195234 Immunol (2018) 9:1009. doi: 10.3389/fimmu.2018.01009
23. Lee HL, Jang JW, Lee SW, Yoo SH, Kwon JH, Nam SW, et al. Inflammatory 49. Zhou X, Yu J, Cheng X, Zhao B, Manyam GC, Zhang L, et al. The
cytokines and change of Th1/Th2 balance as prognostic indicators for hepatocellular deubiquitinase Otub1 controls the activation of CD8(+) T cells and NK cells by
carcinoma in patients treated with transarterial chemoembolization. Sci Rep (2019) 9 regulating IL-15-mediated priming. Nat Immunol (2019) 20(7):879–89. doi:
(1):3260. doi: 10.1038/s41598-019-40078-8 10.1038/s41590-019-0405-2

Frontiers in Immunology 06 [Link]

Wang et al. 10.3389/fimmu.2023.1230465

50. Li W, Qiu S, Chen J, Jiang S, Chen W, Jiang J, et al. Chimeric antigen receptor 63. Bohnacker S, Hildenbrand K, Aschenbrenner I, Muller SI, Bieren JE, Feige MJ.
designed to prevent ubiquitination and downregulation showed durable antitumor Influence of glycosylation on IL-12 family cytokine biogenesis and function. Mol
efficacy. Immunity (2020) 53(2):456–70 e6. doi: 10.1016/[Link].2020.07.011 Immunol (2020) 126:120–8. doi: 10.1016/[Link].2020.07.015
51. Jiang R, Tang J, Chen Y, Deng L, Ji J, Xie Y, et al. The long noncoding RNA 64. Carra G, Gerosa F, Trinchieri G. Biosynthesis and posttranslational regulation of
lnc-EGFR stimulates T-regulatory cells differentiation thus promoting human IL-12. J Immunol (2000) 164(9):4752–61. doi: 10.4049/jimmunol.164.9.4752
hepatocellular carcinoma immune evasion. Nat Commun (2017) 8:15129. doi: 65. Ha SJ, Chang J, Song MK, Suh YS, Jin HT, Lee CH, et al. Engineering n-
10.1038/ncomms15129 glycosylation mutations in IL-12 enhances sustained cytotoxic T lymphocyte responses
52. Chang HM, Yeh ETH. SUMO: from bench to bedside. Physiol Rev (2020) 100 for DNA immunization. Nat Biotechnol (2002) 20(4):381–6. doi: 10.1038/nbt0402-381
(4):1599–619. doi: 10.1152/physrev.00025.2019 66. Sun P, Zhang H, Shi J, Xu M, Cheng T, Lu B, et al. KRTCAP2 as an
53. Wu Q, Zhou L, Lv D, Zhu X, Tang H. Exosome-mediated communication in the immunological and prognostic biomarker of hepatocellular carcinoma. Colloids Surf
tumor microenvironment contributes to hepatocellular carcinoma development and B Biointerfaces (2023) 222:113124. doi: 10.1016/[Link].2023.113124
progression. J Hematol Oncol (2019) 12(1):53. doi: 10.1186/s13045-019-0739-0 67. Chan LC, Li CW, Xia W, Hsu JM, Lee HH, Cha JH, et al. IL-6/JAK1 pathway
54. Yu L, Kim J, Jiang L, Feng B, Ying Y, Ji KY, et al. MTR4 drives liver drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest
tumorigenesis by promoting cancer metabolic switch through alternative splicing. (2019) 129(8):3324–38. doi: 10.1172/JCI126022
Nat Commun (2020) 11(1):708. doi: 10.1038/s41467-020-14437-3 68. Shi HX, Liang C, Yao CY, Gao ZX, Qin J, Cao JL, et al. Elevation of spermine
55. Hou PP, Luo LJ, Chen HZ, Chen QT, Bian XL, Wu SF, et al. Ectosomal PKM2 remodels immunosuppressive microenvironment through driving the modification of
promotes HCC by inducing macrophage differentiation and remodeling the tumor PD-L1 in hepatocellular carcinoma. Cell Commun Signal (2022) 20(1):175. doi:
microenvironment. Mol Cell (2020) 78(6):1192–206.e10. doi: 10.1016/ 10.1186/s12964-022-00981-6
[Link].2020.05.004 69. Liu T, Liu R, Zhang S, Guo K, Zhang Q, Li W, et al. Sorafenib induced alteration
56. Magnelli PE, Bielik AM, Guthrie EP. Identification and characterization of of protein glycosylation in hepatocellular carcinoma cells. Oncol Lett (2017) 14(1):517–
protein glycosylation using specific endo- and exoglycosidases. J Vis Exp (2011) (58): 24. doi: 10.3892/ol.2017.6177
e3749. doi: oi:10.3791/3749 70. Lakshminarayanan V, Thompson P, Wolfert MA, Buskas T, Bradley JM,
57. Vessella RL, Santrach MA, Bronson D, Smith CJ, Klicka MJ, Lange PH. Pathangey LB, et al. Immune recognition of tumor-associated mucin MUC1 is
Evaluation of AFP glycosylation heterogeneity in cancer patients with AFP- achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine. Proc
producing tumors. Int J Cancer J Int du cancer (1984) 34(3):309–14. doi: 10.1002/ Natl Acad Sci U S A (2012) 109(1):261–6. doi: 10.1073/pnas.1115166109
ijc.2910340304 71. Ho V, Lim TS, Lee J, Steinberg J, Szmyd R, Tham M, et al. TLR3 agonist and
58. Pardee AD, Shi J, Butterfield LH. Tumor-derived alpha-fetoprotein impairs the sorafenib combinatorial therapy promotes immune activation and controls
differentiation and T cell stimulatory activity of human dendritic cells. J Immunol hepatocellular carcinoma progression. Oncotarget (2015) 6(29):27252–66. doi:
(2014) 193(11):5723–32. doi: 10.4049/jimmunol.1400725 10.18632/oncotarget.4583
59. Munson PV, Adamik J, Hartmann FJ, Favaro PMB, Ho D, Bendall SC, et al. 72. Mo Z, Yu F, Han S, Yang S, Wu L, Li P, et al. New peptide MY1340 revert the
Polyunsaturated fatty acid-bound alpha-fetoprotein promotes immune suppression by inhibition effect of VEGF on dendritic cells differentiation and maturation via blocking
altering human dendritic cell metabolism. Cancer Res (2023) 83(9):1543–57. doi: VEGF-NRP-1 axis and inhibit tumor growth in vivo. Int Immunopharmacol (2018)
10.1158/[Link]-22-3551 60:132–40. doi: 10.1016/[Link].2018.04.025
60. Wu CJ, Tsai YT, Lee IJ, Wu PY, Lu LS, Tsao WS, et al. Combination of radiation 73. Yang Y, Jin M, Dai Y, Shan W, Chen S, Cai R, et al. Involvement and targeted
and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through intervention of mortalin-regulated proteome phosphorylated-modification in
immunomodulation of tumor microenvironment. Oncoimmunology (2018) 7(9): hepatocellular carcinoma. Front Oncol (2021) 11:687871. doi: 10.3389/
e1477459. doi: 10.1080/2162402X.2018.1477459 fonc.2021.687871
61. Liu Y, Di S, Shi B, Zhang H, Wang Y, Wu X, et al. Armored inducible expression 74. Chen Z, Chen Y, Peng L, Wang X, Tang N. 2,5-dimethylcelecoxib improves
of IL-12 enhances antitumor activity of glypican-3-Targeted chimeric antigen receptor- immune microenvironment of hepatocellular carcinoma by promoting ubiquitination
engineered T cells in hepatocellular carcinoma. J Immunol (2019) 203(1):198–207. doi: of HBx-induced PD-L1. J Immunother Cancer (2020) 8(2):e001377. doi: 10.1136/jitc-
10.4049/jimmunol.1800033 2020-001377
62. Ling P, Gately MK, Gubler U, Stern AS, Lin P, Hollfelder K, et al. Human IL-12 75. Kumar AR, Devan AR, Nair B, Nair RR, Nath LR. Biology, significance and
p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity. J immune signaling of mucin 1 in hepatocellular carcinoma. Curr Cancer Drug Targets
Immunol (1995) 154(1):116–27. doi: 10.4049/jimmunol.154.1.116 (2022) 22(9):725–40. doi: 10.2174/1568009622666220317090552

Frontiers in Immunology 07 [Link]