Post-translational modifications (PTMs) are associated with a large number of cellular processes and regarded as indispensable in maintaining protein function via regulating the activity, stability and localization of proteins (1). As major PTMs, deacetylation and acetylation processes are significant factors in signaling and cellular metabolism (2). The real-life processes of histone acetylation and deacetylation are often regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs), which together participate in numerous dynamic processes and in a wide range of substrate properties such as protein-DNA interactions, transcriptional and metabolic activities, and cell cycle regulation (3). Notably, since a number of significant processes in biology require histone acetylation and deacetylation, such as diabetes, infectious diseases and cancer, the dysregulation thereof is involved in various diseases (4).

In recent decades, owing to the non-negligible effects of acetylation and deacetylation on tumor cell growth and progress, an increasing amount of scientists have investigated acetylation/deacetylation patterns and potential cancer treatment methods (5, 6). Emerging evidence has indicated that suppression of HDACs can potentially inhibit growth and facilitate the differentiation of tumor cells, thereby producing an anticancer effect in HDACs (7). Four compounds (Romidepsin, Belinostat, Panobinostat and Vorinostat) have already been ratified by the Food and Drug Administration (FDA) as HDAC inhibitors (HDACi) for clinical use, with numerous others currently undergoing clinical assessment (8, 9). In the clinical treatment of tumors, immune checkpoints (for instance, CTLA-4, TIM-3, LAG-3, and most importantly, PD-1/PD-L1) have been demonstrated to be effective targets in cancer immunotherapy due to the ability thereof to regulate immune responses (10). Using HDACi alone or in combination with other therapeutic agents such as immune checkpoint inhibitors (ICIs) has been revealed to be effective in cancer immunotherapy, and the significance of acetylation/deacetylation modulation in cancer has attracted much research attention (11).

In the present study, relevant achievements in the field of lysine acetylation/deacetylation modification in cancer immunotherapy were analyzed. First, a brief explanation of the acetylation/deacetylation process and relevant indispensable enzymes that participate therein is provided. Subsequently, a multitude of specific immune-related molecules involved in the lysine acetylation/deacetylation process in the context of cancer are listed, in addition to several therapeutic strategies associated with lysine acetylation/deacetylation modification in cancer immunotherapy. Finally, numerous prospective research fields related with cancer immunotherapy concepts are offered with detailed analysis. The present study may serve as a reference for researchers in the relevant field of study, with the aim of being instructive and meaningful to further research as well as the selection of potential targets and effective measures for future cancer immunotherapy strategies.

Acetylation was discovered in 1963 and has since been extensively investigated by scientists, being regarded as a crucial PTM in cells (12). By neutralizing the positive charge of acetylated lysine sites of histones, which regulates the mutual effect between targeted histones and the DNA skeleton with negative charge, acetylation modulates and relaxes the chromatin structure (13). In recent decades, a number of substrates have been reported as substrates of acetylation in addition to histone, reflecting the universality of acetylation in cellular processes (14). At the same time, a myriad of proteins with bromodomain like transcription factors can be used to identify lysine acetylation marks, which activates the next step of the transcriptional process (15). Deacetylation is the reverse process of acetylation, and is able to create a tighter connection between histone and DNA, causing a more condensed structure of chromatin that blocks the subsequent transcriptional process (16). Notably, lysine deacetylation appears to be a significant factor in chromatin reconstruction, further influencing gene expression and cellular processes (refer to Figure 1 ).

Two groups of essential enzymes are associated with lysine deacetylation and acetylation: histone deacetyltransferases (HDACs) and histone acetyltransferases (HATs). HATs are enzymes that help move the acetyl group from the acetyl coenzyme A to the lysine N-terminal, which removes the basic charge from the unmodified lysine residue, thereby accelerating the resulting active transcription process (17). According to location, HATs can be classified into two types. In the nucleus, Type A HATs are a group of enzymes that facilitate the transcription process by acting as transcriptional activators, which is the common functional feature thereof. The described enzymes can be divided into three separate families depending on the different substrates and functions: the Gcn5-related N-acetyltransferase (GNAT) family, the p300/CREB-binding protein (CBP) family, and monocytic leukemia zinc finger protein, Ybf2/Sas3, Sas2 and Tip60 (MYST) family (18). The p300/CBP family consists of p300 and CBP, which mainly target H3 and H4 residues. The GNAT family consists of PCAF, Gcn5, Hat1, Hpa2 and Elp3, which mainly act on histones. The MYST family includes Tip60, MOF, Esa1, Sas2, Sas3, Hbo1 and MORF, which mainly target H4 residues (19). Acetylation of newly translated histones is associated with cytoplasmic Type B HATs, and such process is essential for the passage of newly synthesized histones across the nuclear membrane into newly replicated DNA. HatB3.1, Rtt109, HAT1, HAT2, and HAT4 are all types of B-type HATs (20). As well as histones, non-histone proteins such as p53 can also be regulated by HATs. In further studies, many other substrates of non-histone proteins were verified to be acetylated (21, 22).

Contrastingly, HDACs are a family of 18 enzymes that exhibit opposite functions to HATs. HDACs remove the acetyl group from lysine residues, which function as corepressors of transcription and reduce the acetylation level of histones. Additionally, several non-histone proteins including c-MYC, p53, and STAT3 can also be deacetylated to regulate cellular processes (23, 24). Gene silencing is caused by lysine deacetylation, which condenses chromatin and limits transcriptional activity (25). HDACs are classified into four types based on the similarity thereof to yeast proteins: Class I, II, III and IV. Class I, II and IV HDACs require the presence of Zn2⁺, while Class III HDACs (also known as sirtuins) are dependent on NAD⁺ (26). Located mainly in the nucleus, a total of four members of Class I HDACs exist: HDAC1, 2, 3, and 8, which are yeast homologs of Rpd3 (27, 28). Class II HDACs can be divided into two groups: Class IIa, which includes HDAC4, 5, 7, and 9, and Class IIb, which includes HDAC6 and 10. The two subclasses are closely related to Hda1 in yeast and can move back and forth between the cytoplasm and the nucleus, allowing Class II HDACs to regulate cytoplasmic substrates (29, 30). Homologous to Sir2 proteins in yeast, Class III HDACs can be categorized into seven elements, including sirtuin (SIRT) 1 to 7. SIRT1, 6, and 7 reside in the nucleus to regulate gene expression by deacetylating substrates (31). SIRT2 has been found to control the cell cycle in both cytoplasm and the nucleus (32, 33). Regarding SIRT3, 4, and 5, said enzymes have been reported to reside in the mitochondria to regulate the activity of oxidative stress (34). A significant characteristic of SIRTs is the ability thereof to not only deacetylate lysine residues but also act as mono-ADP-ribosyltransferases. As such, the enzymes can modulate chromatin, repair DNA and undertake other biological processes (35). In epigenetics, the single member of Class IV HDACs, HDAC11, has emerged as a particular focus of research and is located in the nucleus. Despite preliminary research showing that HDAC11 can negatively modulate IL-10, additional research is required for verification (36).

A number of biological processes including DNA damage repair, immunological response and cell cycle arrest require lysine acetylation/deacetylation. Abnormalities in the acetylation/deacetylation process, such as the dysregulation of the regulating enzymes, have been associated with cancer (37). In previous studies, aberrant expression levels and mutations or translocations of lysine acetylation/deacetylation regulators have been demonstrated in a variety of cancers (38). Acetylation/deacetylation process can modulate immune activity and response via various ways, thus influencing tumor development and progression (refer to Figure 2 ). Several specific immune-related targets of acetylation/deacetylation modification are listed as follows (refer to Table 1 ).

In recent decades, many scholars have found that epigenetic abnormalities, especially dysregulated acetylation or deacetylation, are significant features of various cancers (17). As biological inhibitors that target HDACs that are critical in deacetylation modification, HDACi are used as epigenetic regulatory agents in cancer immunotherapy. By interfering with the activity of HDAC, histone acetylation is indirectly induced to regulate gene expression and modulate host antitumor immune responses. Several studies have shown that HDACi can re-express inactivate regulatory genes in cancer cells and reverse malignant phenotypes (101). By decreasing the levels of FoxP3 and Treg, increasing the cytotoxicity of NK and CD8⁺T cells, and increasing the production of proinflammatory cytokines, HDAC inhibitors are conducive to reducing tumor formation and boosting an efficient immune response against cancer cells (102, 103). At the same time, the normal function of the immune system may be further influenced by HDAC inhibition, which can affect the expression of immune checkpoints and associated ligands. In an SM1 murine melanoma model, the HDAC6 inhibitor greatly reduced PD-L1 and PD-L2 overexpression, which increased the overall survival rate (104). As revealed in another study, HDAC6 inhibition could suppress the T cell expression levels of PD-1, TIM-3 and LAG-3, relieving T cell suppression in melanoma patients (47). The combined application of HDACi and other immunotherapeutic strategies have recently emerged as significant areas of focus in the field of tumor therapy. Several synergistic immunotherapeutic strategies are listed as follows.

Immune checkpoints can effectively suppress immune responses or enable cancers to avoid damage from the entire immune system by activating negative regulatory pathways. Two such immune checkpoints, PD-1/PD-L1 and CTLA-4, have so far received the most attention in cancer immunotherapy. ICIs have made breakthrough progress in many cancer therapeutic fields, bringing new treatment hope to patients. Despite such progress, some patients who use ICIs exhibit no response or even develop drug resistance (105). Studies have shown that HDACi can significantly improve the immune response following the application of ICIs, and can enhance immunity to the effects of treatment. Acetylase inhibitors induce the infiltration of effector T cells, which secrete a variety of immune-related cytokines along with natural killer cells to form a critical line of defense against cancer in the body. HDACi in combination with ICIs have been shown to significantly increase the level of natural killer cells in the tumor microenvironment, resulting in a gradual decrease in tumor cell size (106). Thus, through combined application, HDACi can provide a double guarantee for the efficacy of ICIs by regulating the positive and negative mechanisms of immune response.

Many pre-clinical studies have reported the potential of combining HDACi with ICIs in cancer immunotherapy (refer to Table 2 ). For instance, HDACi in combination with anti-PD-1 or anti-CTLA-4 antibodies were found to promote the production of granase B in activated CD8⁺ T responder cells, significantly improving the infiltration and function of innate immune cells and enhancing adaptive immune response. Using a hepatocellular carcinoma preclinical model, selective HDAC8 inhibition was found to exert effective responses to anti-PD-L1 treatment by reactivating the production of T cell-trafficking chemokines (107). CG-745, a member of HDACi, has been validated to modulate the immune microenvironment and enhance the therapeutic effect of anti-PD-1 ICIs, which indicates the effectiveness of the combined application of HDACi and ICIs (108). In previous studies, the expression level of PD-L1 was increased by HDAC inhibitors, increasing the susceptibility of the host immune system to anti-PD-L1 and anti-PD-1 therapy, and promoting therapeutic results in patients (109). Combining Nexturastat (HDAC6 inhibitor) with an anti-PD-1 agent has been reported to suppress tumor growth, decrease the level of pro-tumorigenic M2 macrophages and upregulate effector T cells in melanoma (104). Moreover, the Class I HDAC inhibitor Etinostat facilitated the positive antitumor effect of PD-1 inhibition in syngeneic mouse models of lung and renal cell carcinoma, which could be attributed to the inhibition of the immunosuppressive functions of myeloid-derived suppressor cells (MDSCs) (110). In a recent study, HDACi Romidepsin was found to upregulate PD-L1 expression and the combined application of Romidepsin and anti-PD-1 antibody could enhance the antitumor therapeutic effect and partially reverse the influence of Romidepsin on CD4⁺ and CD8⁺ T cells in colon cancer (111). Further, the combined application of HDACi and antibodies against CTLA-4 could facilitate CD4⁺T cell infiltration and exert a synergistic effect on cancer treatment by intensifying anticancer immune responses (106).

To further investigate the efficacy of the combined application of HDACi and ICIs, researchers have recently conducted several clinical trials and made progress to a certain degree (refer to Table 2 ). For instance, in metastatic uveal melanoma, the combined application of HDACi Entinostat and PD-1 inhibitor Pembrolizumab has been validated to exert durable responses of tumor regression and prolonged survival in a phase 2 clinical trial, especially for patients with low tumor burden and BAP1 wildtype tumors (124). Further, in a phase 1/1b study, synergizing Vorinostat with Pembrolizumab was well tolerated and exhibited a preliminary anti-tumor effect in advanced/metastatic non-small cell lung cancer (112). The combined application of Tamoxifen, Vorinostat and Pembrolizumab in a phase 2 trial exhibited clinical benefits in terms of the upregulation of exhausted CD8⁺ T cells and the depletion of Tregs, which was linked with better clinical response and prolonged PFS in ER-positive breast cancer patients. Said combination was also well-tolerated without excess toxicity (114). However, in another phase 2 trial involving the combined application of Pembrolizumab and Vorinostat, significant efficacy was reported with a relatively higher grade of toxicity compared with using anti-PD-1 monoclonal antibodies alone in recurrent metastatic head and neck squamous cell carcinomas and salivary gland cancer (113). As such, immunotherapy involving the coadministration of ICIs and HDACi may be essential in prospective cancer treatment. Such immunotherapy may be particularly beneficial for cancer patients who develop drug resistance to immune checkpoint inhibitors. With the in-depth research on the role of HDACi and ICIs in anti-tumor treatment, the synergistic application of HDACi and ICIs may emerge in the broader field of cancer research and eventually in clinical cancer immunotherapy.

Cancer vaccines can be applied in patients with malignant tumors to overcome the immune suppression caused by tumors and activate a patient’s immune system, so as to achieve the purpose of controlling or eliminating tumors (125). As an example, the emergence of the therapeutic HPV DNA vaccine has successfully opened up a new direction for the prevention and treatment of cervical cancer, but the antigenicity of the DNA vaccine itself is weak, and the use of DNA vaccine alone does not have a good anti-tumor effect. The decrease or deletion of MHC Class I molecule expression in cervical cancer cells makes tumor cells unable to recognize and kill CD8⁺T cells, resulting in immune escape. Hence, enhancing the expression of MHC Class I molecules in cervical cancer cells is a significant strategy for cervical cancer immunotherapy. Studies have shown that by increasing the expression of proteins encoded by the DNA vaccine, the combination of HDACi AR-42 and the CRT/E7 DNA vaccine can up-regulate the expression of MHC Class I molecules. Moreover, the expression of MHC Class I molecules can also activate the immune response of CD8⁺T cells, thereby producing effective anti-tumor effects (126).

Using MC38-CEA colon and 4T1 triple-negative breast murine carcinoma models, the combined application of Entinostat (HDACi), N-803 (IL-15 superagonist) and cancer vaccine was found to promote an anticancer effect by facilitating the infiltration of activated CD8⁺T cells and activating T cell responses to various tumor-associated antigens in the tumor microenvironment (127). Additionally, the synergistic inhibition of HDAC and proteins of bromodomain and extraterminal (BET) can also enhance the vaccine-induced CD8⁺T cell response and promote the therapeutic effect in melanoma treatment (128). Therefore, the combined application of HDACi and cancer vaccines may have promising prospects in clinical cancer immunotherapy (refer to Table 3 ). However, in addition to HDACi and cancer vaccines, other therapeutic agents were involved in the aforementioned studies. Further studies are needed to confirm whether applying HDACi alone with cancer vaccines can produce the same treatment effect in cancer immunotherapy.

Therapeutic antibodies are laboratory-made antibodies designed to destroy tumor cells in different ways, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct induction of apoptosis by antibodies (133). Several therapeutic antibodies have been approved for the clinical treatment of cancer. In 1997, Rituximab (Rituxan), the first chimeric antibody against CD20, was approved by the FDA for the treatment of non-Hodgkin’s lymphoma. Trastuzumab (Herceptin), the first humanized anti-HER2 monoclonal antibody, was marketed in 1998 for the treatment of breast cancer. Several other directly targeted antitumor antibodies, such as Panitumumab, Cetuximab, and Adesimab, have since received FDA approval for anticancer effects in cancer immunotherapy (134–136).

The combination of HDACi and antitumor antibodies has been reported to enhance antitumor responses and promote the therapeutic efficacy of cancer immunotherapy in numerous studies. By blocking the Akt signaling pathway and increasing DNA breakage, the HDAC Class I inhibitor sNDX-275 can significantly promote Trastuzumab-induced growth inhibition in erbB2-overexpressed breast cancer cells, which may also overcome Trastuzumab resistance in breast cancer immunotherapy (129). Treatment with the HDAC inhibitor Chidamide in synergy with Rituximab was found to significantly upregulate CD20 and inhibit the growth of diffuse large B-cell lymphoma (DLBCL) in vitro and in vivo, confirming that Chidamide may have application prospects in DLBCB immunotherapy (130). A similar study confirmed the effectiveness of the combination of HDACi and antitumor antibodies, in which Entinostat was reported to promote the anticancer effects of Rituximab and chemotherapeutic agents in B-cell lymphoma (131). Another HDACi, Vorinostat, enhanced cell cycle arrest and restored the sensitivity of Rituximab-resistant lymphoma cells to chemotherapeutic drugs (132). Thus, the synergistic application of HDACi and antitumor antibodies may provide a new direction for improving the effectiveness of immunotherapy in cancer treatment (refer to Table 3 ).

As a significant epigenetic regulatory mechanism, acetylation/deacetylation has been found to well regulate the process of gene expression transcription and modulate the host immune response in various cancers, further aiding tumor development and progression by regulating the expression of oncogenes or tumor suppressor genes and weakening the anti-tumor immune response (137). Numerous studies have reported that targeting HATs and HDACs that are essential in the acetylation/deacetylation process can modulate epigenetic signaling pathways and recover the normal expression level of numerous cancer-related genes and anti-tumor immune responses, thereby offering treatment benefits in cancer immunotherapy (138).

Among the various substances that can target HATs/HDACs directly, or those associated with molecules in acetylation/deacetylation-relevant signaling pathways, HDAC inhibitors have become a large focus of research and been applied with various degrees of success in different settings to treat cancer (139). Since 2006, four different types of HDAC inhibitors have been authorized by the FDA for clinical use, and over 20 different HDAC inhibitors are currently being tested in clinical studies (140). Notably, as a trending field in oncology research, the therapeutic effect of cancer immunotherapy can be elevated in combination with HDAC inhibitors, showing the significance of combining multiple therapeutic methods in the practice of cancer treatment. The efficacy of HDAC inhibitors can be promoted by means of the synergetic application of numerous immunotherapeutic approaches, including cancer vaccines, immune checkpoint inhibitors and others (141).

Many immune-related molecules are not only modified by acetylation/deacetylation, but also by other PTMs such as phosphorylation, ubiquitination, and methylation to regulate the expression level thereof and further modulate host immune responses. Examples include phosphorylated PD-L1 by glycogen synthase kinase 3β (GSK3β), which can be further degraded by ubiquitin-proteasome system and Olaparib, a PARP1 inhibitor that maintains and upregulates the expression level of PD-L1 in cancers by suppressing the activity of GSK3β, thereby inhibiting the antitumor immune response and facilitating the tumor immune escape (142). Additionally, acetylation/deacetylation can act synergistically with other types of PTMs on an immune-related molecule to regulate the expression thereof. Consistently Photomorphogenic 1 (COP1) is a ubiquitin E3 ligase, and the reduction thereof can inhibit c-Jun ubiquitination degradation, maintain the stability and facilitate phosphorylation by C-Jun N-terminal kinase (JNK), further promoting the translocation of c-Jun into the nucleus and suppressing the production of HDAC3. Such effects result in a looser chromatin structure by acetylation and increases the expression of PD-L1 (143). Hence, the improvement of anticancer immunotherapeutic efficacy may be achieved through the combination of multiple drugs acting on diverse PTMs or the application of a single chemical compound that targets various substrates. The synergistic application of drugs that modulate acetylation/deacetylation and other PTMs represents a promising treatment approach in future cancer immunotherapy.

Despite a number of researchers having reported anticancer effects in immunotherapy that targets the acetylation/deacetylation process and related molecules, there are still questions that warrant further investigation. For instance, numerous immune-related molecules that regulate antitumor immune responses have not been reported to be altered by acetylation or deacetylation. T-cell immunoglobulin and the ITIM domain (TIGIT) is an emerging immune checkpoint that suppresses innate and adaptive immunity, thereby inhibiting antitumor immune responses. The combined application of drugs that block TIGIT and PD-1 (Atezolizumab/Tiragolumab) can upregulate CD8⁺ T cell expression and function, which may be considered as a potential cancer immunotherapy strategy (144). Another immune regulatory protein, V-domain Ig suppressor of T cell activation (VISTA), can maintain quiescence on T cells and myeloid-derived cells. In a CT26 colon cancer mouse model, immunotherapy applied in combination with VISTA and PD-L1 ICIs contributed to tumor regression and led to long-term survival in the mouse model, demonstrating the rationale for targeting VISTA in cancer immunotherapy. Further studies of acetylation/deacetylation modifications of immune-related molecules, such as the aforementioned novel immune checkpoints, may facilitate broader ideas and more effective therapeutic strategies for future cancer immunotherapy. Further, many cytokines have also been found to participate in the regulation of immune homeostasis and response such as transforming growth factor (TGF)-β, IFN-γ and others. TGF-β can enhance the expansion of Tregs and suppress the function of effector T cells, causing immune evasion in tumor microenvironments and poor responses to cancer immunotherapy (145). IFN-γ is crucial for NK, NKT, and T cells trafficking into tumors, which regulates the immune response and tumor progression (146). Targeting the acetylation/deacetylation process to modulate the expression of the aforementioned critical cytokines may relieve immunosuppression and reactivate the immune response in the tumor microenvironment, thereby promoting the efficacy of cancer immunotherapy.

Regarding the existing studies on the regulation of immune-related molecules by acetylation or deacetylation, the focus has mostly been on the regulatory effect of HDACs, and there is a scarcity of studies on the modification of immune-related molecules by HATs. In the clinical practice of cancer immunotherapy, HDACi have been approved and demonstrated to be valid in cancer treatment. However, unlike HDACi, HAT inhibitors have not been applied in clinical therapy and can be regarded as being stagnant in experimental phases. CCS1477, for example, is the only CBP/p300 inhibitor currently undergoing clinical trials. Even if HAT inhibitors have an essential function in tumor suppression and may exhibit a potential immunotherapeutic effect in cancer treatment, the significance of HAT inhibitors has been well-covered by the in-depth research on HDACi. HAT inhibitors and the modification signaling pathways through which HATs regulate immune-related molecules are of equal significance and deserve the attention of more scientists.

Moreover, a further challenge that inhibits the utilization of HDAC inhibitors is the adverse effects and toxicity observed in early-phase clinical trials. Taking HDACs as an example, only 18 HDACs are responsible for modulating a large number of lysine acetylation residues in over 2000 proteins. Even though HDAC inhibitors can reactivate tumor suppressors, there will be a negative effect on other genes. Future strategies should be directed at developing selective inhibitors to target specific acting sites rather than enzymes, with the aim of overcoming drug toxicity and resistance in cancer immunotherapy.

In addition, the focus of most clinical trials has been on the combination of HDACi and ICIs, and there are fewer clinical studies on the anti-tumor efficacy of HDACi combined with cancer vaccines and antitumor antibodies. Future studies on such aspects may provide new strategies for cancer immunotherapy.

In summary, as a significant PTM, lysine acetylation/deacetylation mediated by HATs/HDACs is crucial in regulating various signaling pathways, and also in modulating cancer development and progression by regulating host antitumor immune responses (refer to Figures 3 , 4 ). Owing to the indispensability thereof, lysine acetylation/deacetylation has received an increasing amount of attention from scientists. The aim of research in the relevant field is to find efficient methods for clinical cancer immunotherapy. Although targeting crucial enzymes in the acetylation/deacetylation pathway, such as HATs/HDACs, has been shown to recover immune response to exert a cancer therapeutic impact, and certain HDAC inhibitors have even been licensed by the FDA for clinical use, there are still a number of issues to be resolved. The elucidation of detailed molecules in the acetylation/deacetylation pathway, the discovery of new HAT/HDAC targeted compounds, and the combination of HAT/HDAC inhibitors with other drugs, such as immune checkpoint inhibitors, can all contribute to the finding of new targets and ideas for future cancer immunotherapy.

XY, JH, and JW designed the study. PD, ZM, DLi, MP, and HL searched the literature and wrote the manuscript. YF, YZ, CS, MJ, and DLu searched the literature and made the table, and PD draw the figures. All authors read and approved the final manuscript.

This work was supported by the National Natural Science Foundation of China (82103508, 81871866, 82173252), Shaanxi Special Support Plan-Program for Leading Talents of Science and Technology Innovation (No. 2019 Special Support Plan), the Natural Science Foundation of Shaanxi Province (2016SF-308, 2019SF-033, 2021SF-158, 2022SF-145) and Project of Tangdu Hospital, the Air Force Military Medical University (No. 2018 Key Talents).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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