
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)11932-9
10.1016/j.heliyon.2024.e35901
e35901
Review Article
IL-22: A key inflammatory mediator as a biomarker and potential therapeutic target for lung cancer
Xu Ling a1
Cao Peng a1
Wang Jianpeng b1
Zhang Peng a
Hu Shuhui a
Cheng Chao a
Wang Hua wanghua@ahmu.edu.cn
c⁎
a Department of Interventional Pulmonary Diseases, The Anhui Chest Hospital, Hefei, China
b First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
c Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
⁎ Corresponding author. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China. wanghua@ahmu.edu.cn
1 These authors have contributed equally to this work and share first authorship.

10 8 2024
15 9 2024
10 8 2024
10 17 e3590113 8 2023
5 8 2024
6 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Lung cancer, one of the most prevalent cancers worldwide, stands as the primary cause of cancer-related deaths. As is well-known, the utmost crucial risk factor contributing to lung cancer is smoking. In recent years, remarkable progress has been made in treating lung cancer, particularly non-small cell lung cancer (NSCLC). Nevertheless, the absence of effective and accurate biomarkers for diagnosing and treating lung cancer remains a pressing issue. Interleukin 22 (IL-22) is a member of the IL-10 cytokine family. It exerts biological functions (including induction of proliferation and anti-apoptotic signaling pathways, enhancement of tissue regeneration and immunity defense) by binding to heterodimeric receptors containing type 1 receptor chain (R1) and type 2 receptor chain (R2). IL-22 has been identified as a pro-cancer factor since dysregulation of the IL-22-IL-22R system has been implicated in the development of different cancers, including lung, breast, gastric, pancreatic, and colon cancers. In this review, we discuss the differential expression, regulatory role, and potential clinical significance of IL-22 in lung cancer, while shedding light on innovative approaches for the future.

Graphical abstract

Structure and main content of the review.Image 1

Highlights

• IL-22 plays a role in the development and progression of lung cancer by regulating certain signaling pathways.

• Blocking IL-22R1 or knocking down IL-22 gene can delay the progression of lung cancer.

• The combination of IL-22 with gene editing and novel nanomaterials has a promising future in the treatment of lung cancer.

Keywords

IL-22
Lung cancer
Biomarker
Inflammation immunology
==== Body
pmc1 Introduction

Lung cancer is a heterogeneous disease in which cells in the lung grow aberrantly culminating in the formation of tumors. Typically, these tumors present as nodules or masses discernible through pulmonary imaging techniques [1]. In the year 2020, the global incidence of lung cancer surpassed a staggering 2.2 million cases, leading to approximately 1.8 million tragic fatalities. When considering age-standardized rates, the morbidity and mortality figures stand at 22.4 and 18.0 per 100,000 individuals respectively [2]. Generally, lung cancer is considered to be intricately linked to a multitude of factors including but not limited to smoking, genetic predisposition, occupational exposures, as well as the deleterious effects of air and environmental pollution [3,4]. Among the risk factors for lung cancer, smoking dominates overwhelmingly, with about two-thirds of lung cancer deaths globally caused by it [5]. In recent years, the drug resistance phenomenon of lung cancer to chemotherapy and targeted therapy has become more and more prominent [[6], [7], [8]]. Therefore, it is of heightened importance to find new therapeutic targets.

IL-22 is an IL-10 family cytokine produced by T cells and innate lymphocytes. Like all other IL-10 family members, the IL-22 structure contains six α-helices (termed helices A to F). They are arranged in an antiparallel conformation and produce a single bundled protein [9]. IL-22 coordinates mucosal immune defense and tissue regeneration through pleiotropic effects including prosurvival signaling, cell migration, dysplasia, and angiogenesis. These molecules act by targeting the heterodimeric transmembrane receptor complex composed of IL-22R1 and IL-10R2 and by activating subsequent signaling pathways (including JAK/STAT signaling pathway, p38 MAPK signaling pathway, and PI3K/AKT signaling pathway) [10]. It is well known that IL-22 is widely expressed in human tissues and organs, including lung, liver, heart, kidney, pancreas, gastrointestinal tract, skin, blood, adipose, and synovial tissues [11]. Meanwhile, IL-22 is also found to be broadly expressed in pathological states such as cancer, infectious diseases, tissue injury, chronic inflammatory diseases, and Graft-Versus-Host Disease [[11], [12], [13], [14]]. In most cancer diseases, excessively elevated levels of IL-22 are considered to be detrimental [[15], [16], [17], [18], [19]]. For instance, a recent study has demonstrated that IL-22 promotes extravasation of tumor cells in liver metastasis [20]. Over the past few years, there has been a surge in research focusing on the relationship between IL-22 and lung cancer. Particularly in patients with NSCLC, researchers have discovered up-regulated expression of IL-22 in serum, malignant pleural effusion, and tumor tissues, and the levels of IL-22Rα1 in tumor cells and tissues are also increased [[21], [22], [23], [24]].

Although emerging studies have revealed that IL-22 is closely correlated with lung cancer in terms of tissue, cell and pathological changes, the specific function and mechanism remain to be explored. In the present review, we mainly summarized the regulatory function and clinical role of IL-22 in lung cancer. In addition, the feasibility of IL-22 as a biomarker for lung cancer and directions for future research were also discussed. It is reasonable to hypothesize that IL-22 may serve as a potential target in the treatment of lung cancer.

2 Overview of lung cancer

Lung cancer is a malignant disease characterized by high morbidity and mortality [25]. According to the data of GLOBOCAN, lung cancer is the second most common cancer in 2020 and the main cause of cancer death worldwide, with about one-tenth (11.4 %) of cancer diagnoses and one-fifth (18.0 %) of deaths [5]. When it comes to gender, the incidence and mortality rates of lung cancer were on the rise in females but declining in males in most countries over the past decade [2]. The 5-year survival rate of lung cancer patients varies by 4–17 % in light of stage and region [26]. As predicted by the American Cancer Society, more than 120,000 people will die of lung cancer in the United States in 2023. The good news is that although the incidence is stable or increasing, the overall mortality is decreasing at an accelerated pace [27]. From the perspective of histopathology and biological behavior, lung cancer can be divided into NSCLC and SCLC, among which the former mainly includes several common types such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma [25]. The pathogenesis of lung cancer primarily involves the following aspects: chromosome changes; abnormal immune response; abnormal activation of developmental pathways; dysregulation of tumor suppressor genes, proto-oncogenes, and signaling pathways; and the up-regulation of receptor tyrosine kinases, growth factors, and cell markers. These abnormal changes cause an imbalance between lung cell proliferation and apoptosis, which leads to lung cancer [[28], [29], [30], [31]]. For example, when exposed to risk factors continuously, the production of ROS, chemokines, and cytokines increases in lung cells, which leads to DNA damage and gives rise to inflammation and other pathobiological changes that ultimately promote carcinogenesis. At the same time, the anti-tumor immune function of macrophages, T lymphocytes, B lymphocytes, and NK cells gets suppressed, failing recognition and clearance of malignant cells, and eventually bringing about the formation of tumors [32]. In the early stage of the disease, it is usually considered to be asymptomatic, while may manifest as cough, dyspnea, chest pain, hemoptysis, hoarseness, and so on in the middle and advanced period [33]. In principle, the treatment of lung cancer depends largely on the type, stage and condition of the patient's disease. Currently, the main treatment approaches for lung cancer include surgery, chemotherapy, and radiotherapy. Among them, platinum-containing double drugs are preferred for chemotherapy. Radiation therapy is mainly applied in the control of the local lesion. Furthermore, targeted therapy for EGFR, ALK, ROS1, and other gene mutations and immunotherapy to inhibit PD-1/PD-L1 also plays an irreplaceable role as emerging breakthrough therapeutic means [25,[34], [35], [36], [37], [38], [39]]. Compared with chemotherapy, targeted therapy can prominently enhance the survival rate and tolerance of patients with NSCLC [40,41]. The combination of chemotherapy and immunotherapy has also shown a more notable curative effect over chemotherapy alone [42,43]. Additionally, there has been a growing body of research focusing on natural product therapy, local ablative therapy, and chimeric antigen receptor (CAR)-T-cell therapy lately [[44], [45], [46], [47], [48], [49], [50], [51]]. In principle, the treatments of lung cancer are individualized depending largely on the type, stage, and condition of patients. Unfortunately, the limited sensitivity of NSCLC patients to chemotherapy and immunotherapy drugs has proven to be a major obstacle to clinical treatment. Denk D et al. suggested that inflammation is ubiquitous in carcinogenesis. In his study, he noted that interfering with individual cytokines and their respective signaling pathways holds great promise for the development and improvement of current clinical cancer therapies [52]. IL-22 is a new type of cytokine discovered in 2000 and has gradually attracted attention due to its role in tumor diseases. In recent years, multiple studies have reported the positive role of IL-22 in enhancing chemotherapy resistance in human lung cancer patients. This positive effect is related to the function of IL-22 in promoting lung cancer cell proliferation and inhibiting lung cancer cell apoptosis. Results showed that IL-22 activated the EGFR/AKT/ERK signaling pathway [52], STAT3, and ERK1/2 signaling pathways [24] in drug-treated lung cancer cells, thereby attenuating the pro-apoptotic effect of the drug on lung cancer cells.

3 Function role of IL-22 in lung cancer

IL-22 is a cytokine first identified by Dumoutier et al. in IL-9-induced murine T cells over 20 years ago and was once called IL-10-related T cell-derived inducible factor (IL-10-TIF) [53]. In human-beings, the IL-22 gene lies in chromosome 12q15, next to the gene that encodes IFN-γ [54]. When the body is in homeostasis, the most important source of IL-22 is Group 3 innate lymphoid cells (ILC3) [14]. Different from other common cytokines, IL-22 is generally thought to be produced only by hematopoietic origin immune cells, whereas it mainly acts on non-hematopoietic cells due to its receptor distribution [55]. Recently, researchers have found that non-hematopoietic cells represented by fibroblasts can also produce IL-22 under certain circumstances [11]. IL-22 is known to act by binding to its receptor (IL-22R), which is synthesized from the IL-22R1 and IL-10R2 subunits [56]. Thereinto, IL-22R1 expression is thought to be restricted to epithelial cells in organs such as the lung, liver, intestine, and skin, while the latter is universally expressed [11,57]. IL-22BP, also known as IL-22RA2, is a soluble IL-22 receptor that binds specifically to IL-22 and prevents it from binding to IL-22R1. All currently known functions of IL-22BP are achieved by inhibiting IL-22 [58,59]. Broadly speaking, the primary function of IL-22 in the body is to promote cell proliferation and tissue protection [60]. Sometimes, excessive activation of this function may lead to pathological results. This dual effect is reflected in both inflammatory and tumor-related diseases. In the short term, the production of IL-22 can play a protective role in anti-inflammatory and tumor prevention, while the uncontrolled generation of IL-22 may promote inflammation and tumor formation [13,18]. The duality of IL-22 reveals that it could be a potential drug target, and the tight regulation of IL-22 is crucial in the treatment of a variety of diseases. In Fig. 1, We summarize the role of IL-22 in lung cancer.Fig. 1 IL-22 plays four main functions during the progression of lung cancer. 1) Promote lung cancer cell proliferation and invasion, and inhibit lung cancer cell apoptosis; 2) Regulate the abundance of immune cells in lung cancer tissues and activate the inflammatory microenvironment; 3) Promote cancer angiogenesis; 4) Activate lung cancer stem cells.

Fig. 1

In general, the expression levels of IL-22 in vivo are regulated by a variety of cytokines and genes. For instance, IL-1β and IL-23 can induce the production of IL-22 independently, and the two act synergistically [11]. What's more, Cornelia Voigt described a novel mechanism whereby cancer cells promote tumor growth by releasing IL-1β to induce IL-22 production by memory CD4+ T cells [61]. According to an animal experiment, IL-1β can enhance the proliferation of epithelial cells and promote lung tumorigenesis [62]. IL-23 has been proven to promote proliferation in NSCLC by Anne-Marie Baird et al. [63]. Although IL-23 is thought to be able to induce macrophages to produce IL-22, this study by Anne-Marie Baird et al. cannot directly prove whether the proliferation-promoting effect of IL-23 on NSCLC cells is related to IL-23's promotion of IL-22 production. related to ability. IL-23 is also thought to promote the expression of IL-26 by macrophages. Like IL-22, IL-26 is part of the IL-10 family. Researchers demonstrated for the first time that IL-26 is involved in the generation of malignant pleural effusions [64]. They reported that IL-26 promotes the generation of malignant pleural effusion by mediating the infiltration of CD4+IL-22+T cells in malignant pleural effusion and stimulating CD4+ IL-22+ T cells to secrete IL-22. Recently, the Notch-AhR-IL-22 axis is thought to be involved in the pathogenesis of LUAD. It is corroborated that in LUAD patients, elevated Notch1 facilitates IL-22 generation by CD4+ T cells via aryl hydrocarbon receptors (AhR) [65]. In NSCLC, Notch signaling can both promote tumorigenesis and inhibit tumor progression, which mainly depends on its regulation of the transformation between neuroendocrine and non-neuroendocrine. For patients with SCLC containing Notch active tumor cells, the application of Notch inhibitors may be an effective treatment [66]. Moreover, the expression of IL-22 is also regulated by miR-26. In cutaneous T-cell lymphoma (CTCL) cells, transfection of miR-26 resulted in a remarkable decrease in the expression levels of IL-22 and IL-22 mRNA [67]. In human NSCLC, Yi He et al. found that the expression levels of miR-26 were lower in tumor tissues compared to paracancerous tissue. As a functional miRNA, miR-26 was further proved by the team to inhibit autophagy and induce apoptosis of NSCLC cells both in vitro and in vivo [68]. On the other hand, IL-22 has also been shown to regulate other cytokines. Studies have shown that the production of IL-22 generally reduces Th1-type immune responses. This action may be coordinated with the protective effect of IL-22R-expressing tissue cells to reduce collateral damage in the context of infection and inflammation [69]. Besides, animal experiments have indicated that IL-22 can also promote B-cell responses by inducing CXCL13 in tertiary lymphoid follicles [70,71]. In the latest murine lung cancer model, IL-22 was discovered to induce NK cells to overexpress CD155, thus mediating the immune evasion of tumor cells [72]. As a transmembrane adhesive molecule, CD155 has been proven to inhibit T and NK cell-mediated anti-tumor immune responses, thereby promoting tumor progression (Fig. 2) [[73], [74], [75]].Fig. 2 IL-22 induces NK cells to overexpress CD155, which binds to NK cell activation receptor CD226. Over-activation leads to a decrease in the amount of CD226 and impaired NK cell function, thereby mediating tumor cell immune escape.

Fig. 2

In the occurrence and development of pulmonary diseases, IL-22 is considered to play an important role. As previously demonstrated in an epicutaneously sensitized mice experiment, IL-22 promotes the development of neutrophil and eosinophile-mediated airway inflammation and airway hyperresponsiveness stimulated by intranasal antigens [76]. The conclusion implies that blocking IL-22 may be helpful for the treatment of bronchial asthma. When it comes to chronic obstructive pulmonary disease (COPD), the expression levels of both IL-22 and its receptor in COPD patients were higher than those of healthy controls. This result was confirmed in mice with experimental COPD induced by cigarette smoke. What's more, researchers also found that cigarette smoke-induced inappropriate activation of pulmonary neutrophils decreased in IL-22-deficient mice with COPD. This suggests that IL-22 may be involved in the pathogenesis of COPD. The research further manifested that IL-22 promotes cigarette smoke-induced airway remodeling, pulmonary neutrophil inflammation, and the impairment of pulmonary function, and is involved in the pathogenesis of COPD [77]. While in pulmonary infectious diseases such as pneumonia, tuberculosis, and pulmonary mycosis, it is thought that IL-22 appears to take a protective and preventive part [[78], [79], [80], [81], [82], [83]]. For good measure, in the bleomycin-induced pulmonary fibrosis model, the degree of pulmonary fibrosis in IL-22 knockout mice was aggravated, and injection of recombinant IL-22 alleviated the severe fibrosis in IL-22 knockout mice. This latest research has suggested the potential antifibrotic effect of IL-22 [84].

In recent years, differential expression of IL-22 has also been discovered in various specimens of lung cancer (Table 1). In the first place, the mean levels of IL-22 in the plasma of NSCLC patients were significantly higher than that of the reference cohort [21,85]. The plasma levels of IL-22 were observed to elevate along with the increase in lung cancer staging [85]. In addition, Immunohistochemistry analysis showed that IL-22 expression was up-regulated in NSCLC tumor specimens in comparison to that in the adjacent tissues. RT-qPCR analysis also revealed similar differences in IL-22 mRNA expression between lung cancer tissues and normal tissues [24,86]. Interestingly, Yi Bi et al. compared IL-22 levels between tissues and serum of patients with primary NSCLC and their paired recurrent lung cancer specimens and the expression levels of IL-22 were found to be obviously up-regulated in the latter group [23]. Apart from this, IL-22 expression was also detected in bronchoalveolar lavage fluid (BALF). As reported by an article in 2016, IL-22 levels were significantly higher in BALF from lung cancer patients compared with control group. The researchers expanded the cohort to patients with lung metastases from other malignancies and found that IL-22 concentrations remained higher than controls [87]. These results implied that IL-22 in BALF may be a biomarker for lung cancer. Over and above, researchers also found the trace of IL-22 in pleural effusion [88,89]. One study has revealed that IL-22 levels were higher in malignant pleural effusion as against tuberculous pleural effusion [24]. These differential expressions prompt that IL-22 may participate in the occurrence and development of lung cancer (Table 2).Table 1 Differential expression of IL-22/IL-22 mRNA/IL-22R1 mRNA in various samples in lung cancer. +: Up-regulated.

Table 1Molecule	Samples	Expression	P value	Ref. (PMID)	
IL-22	Plasma	+	0.0013	24956177	
IL-22 mRNA	Tissues	+	0.0313	18927282	
IL-22	Pleural effusion	+	0.0051	18927282	
IL-22 mRNA, IL-22	Tissues, serum	+	<0.01	26983629	
IL-22R1 mRNA	Tissues	+	<0.05	26983629	
IL-22	BALF	+	<0.001	27388918	

Table 2 Potential clinical role of IL-22, its receptors and producing cells in lung cancer.

Table 2Sample sources	Clinical function	Conclusion	Ref. (PMID)	
Patients	Diagnosis	IL-22 levels were significantly higher in lung cancer patients than control group.	24956177,
27388918	
Patients	Prognosis assessment	IL-22R1 levels were associated with poorer prognosis.	26846835	
Patients	Disease assessment	The levels of IL-22-producing Th22 cells were positively correlated with TNM stage and lymph node metastasis.	35669104	
Patients	Efficacy prediction	IL-22 expression levels were associated with EGFR-TKI efficacy.	31750252	
Mice model	Treatment	IL-22-deficient mice had a lower metastatic load of lung cancer.	36630913	
Mice model	Treatment	Gene ablation of IL-22 resulted in a marked reduction in the number and size of lung tumors.	29764837	

The link between inflammatory processes and cancer has long been recognized [90]. Related studies hint that inflammatory responses play a vital role in different phases of tumor occurrence, development, and metastasis [[91], [92], [93]]. The function of IL-22 in cancer is extremely complicated. Initially, IL-22 may prevent tumorigenesis by reducing chronic inflammation, promoting barrier function, and inducing tissue regeneration. On the contrary, if IL-22 is excessively expressed under persistent chronic inflammation, then malignant cells may utilize this signal to facilitate its progression [11]. In the lung tumor microenvironment, uncontrolled expression of IL-22 can amplify inflammation by inducing various inflammatory mediators alone or in concert with other cytokines [94]. As illustrated by a cellular experiment, IL-22 could promote the proliferation of A549 and H125 cells belonging to the NSCLC cell lines, thereby enhancing the ability of tumor cell migration and invasion [23]. An in vitro experiment in 2018 has confirmed that IL-22 can directly act on endothelial cells to stimulate tumor angiogenesis [95]. To some extent, this enhances the ability of tumor cells to absorb nutrients and distant metastasis. From another perspective, this provides new ideas for anti-angiogenic therapy of tumors. Nasim Khosravi suggested that IL-22 promotes tumor progression by inducing a pro-tumor immune response and protective stem cell properties of tumor cells [94]. It is also reported that after 12h of serum starvation, the proportion of apoptotic lung cancer cells transfected with the IL-22 gene was significantly lower than that of control lung cancer cells. In addition, the apoptosis-inducing and anti-proliferative effects of chemotherapeutic drugs on lung cancer cells were inhibited in IL-22 transgenic cell lines [24]. Simultaneously, the apoptosis of lung cancer cells induced by gefitinib was also significantly reduced 48 h after IL-22 exposure [96]. On the contrary, exposure to IL-22R1 blocking antibodies or in vitro transfection of IL-22-RNA interference plasmid leads to apoptosis of lung cancer cells [24]. Zhiliang Huang et al. found that the apoptosis rate of paclitaxel-treated lung cancer cells in the IL-22 siRNA transfection group was significantly increased compared with the control group [22]. Apart from this, IL-22 antibody treated mice and IL-22-deficient mice were found to be protected from the formation of pulmonary metastases caused by colon cancer, while IL-22 overexpression promoted metastases [20]. In short, IL-22 not only antagonizes the induction of apoptosis and cell cycle arrest of lung cancer cells by anti-tumor drugs but also promotes the proliferation and migration of lung cancer cells, the growth of tumor tissues, and the generation of lung metastatic cancer.

4 Regulatory role of IL-22 in lung cancer

Numerous signaling pathways are involved in the regulation of IL-22 in lung cancer, including PI3K/AKT, JAK-STAT3, p38 MAPK signaling pathways, and so on. In the following, we will elaborate on the regulatory role of IL-22 in lung cancer from the point of view of each major signaling pathway (Fig. 3).Fig. 3 IL-22 promotes the proliferation, migration and epithelial-mesenchymal transition of lung cancer cells through PI3K/AKT, JAK-STAT3, p38 MAPK and other signaling pathways, and antagonizes the apoptosis of lung cancer cells induced by anti-tumor drugs.

Fig. 3

4.1 PI3K/Akt signaling pathway

PI3K/AKT signaling pathway is one of the core intracellular signaling pathways, which plays a critical role in regulating cell growth, survival, metabolism, movement, and proliferation [97]. As a downstream effector of receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs), PI3K is a group of lipid kinases consisting of three subunits. It can be divided into three categories according to various functions and structures. Thereinto Class IA PI3K is a heterodimer of the p110 catalytic subunit and the p58 regulatory subunit, and it is primarily related to human tumors [98,99]. As we all know, PI3K can catalyze phosphatidylinositol [4,5]-bisphosphate (PIP2) to phosphatidylinositol [[3], [4], [5]]-trisphosphate (PIP3). Serine/threonine protein kinase (AKT), as the main downstream molecule of the PI3K signaling pathway, is mainly activated by PIP3-driven plasma membrane recruitment and phosphorylation. The mammalian target of rapamycin (mTOR), a major downstream signaling molecule in the PIK3/AKT signaling pathway, is considered to be a modified protein kinase in the form of mTORC1 and mTORC2. The first is mainly activated by the PI3K/AKT signaling pathway, and mTORC2 further activates AKT by directly phosphorylating its hydrophobic motif (Ser473) [100]. PI3K/Akt signaling pathway is considered to be the chief regulatory factor of idiopathic pulmonary fibrosis (IPF), it may directly participate in the formation of IPF or promote the occurrence and development of fibrosis in collaboration with other pathways [97]. Several studies have declared that certain natural products like resveratrol and Danhong injection can provide neuroprotective effects by activating the PI3K/AKT/mTOR signaling pathway [101,102]. Furthermore, the relationship between the PI3K/AKT/mTOR signaling pathway and cancer has been most intensively studied. Activation of the PI3K/AKT/mTOR signaling pathway is believed to promote the occurrence, proliferation, and progression of a variety of cancers, including breast cancer, ovarian cancer, prostate cancer, etc. [99,100,103]. In addition, it is also an important cause of tumor drug resistance [104]. In NSCLC, KRAS, EGFR, and PTEN mutations are believed to activate the PI3K/Akt/mTOR signaling pathway [105]. As demonstrated in a previous article, upregulation of the PI3K signaling pathway was identified as an early and reversible event in the pathogenesis of NSCLC [106]. One experiment has confirmed that the PI3K/AKT signaling pathway promotes the proliferation of LUAD cells mainly through anti-apoptosis [107]. Additionally, as revealed in a cellular study, IL-22 produced by CAFs markedly improves the proliferation and invasion of lung cancer cell, and lessens apoptosis by activating the PI3K/Akt/mTOR signaling pathway [86]. For good measure, it has been found that AKT phosphorylation in NSCLC cells is facilitated by different concentrations of IL-22 in a time- and dose-dependent way [23]. Collectively, the PI3K/Akt/mTOR signaling pathway plays a significant role in the relationship between IL-22 and lung cancer. It is worth mentioning that IL-22 does not seem to always activate the PI3K/Akt/mTOR signaling pathway. Meng Yuxia et al. found that IL-22 inhibits the activity of the PI3K/AKT/mTOR signaling pathway in mouse liver fibrosis tissue [108]. This opposite finding may be related to the dual function of IL-22. Further study on the impact of IL-22 on the PI3K/AKT/mTOR signaling pathway in different disease processes will help us better understand the specific mechanism of IL-22's function in the human body. This will facilitate IL-22-related clinical drug development.

4.2 JAK/STAT signaling pathway

The JAK/STAT signaling pathway is also an important communication center for cell function, and aberrant alterations in its components are associated with numerous human diseases. JAK/STAT is an evolutionarily conserved signaling pathway consisting of JAKs, STATs, and ligand-receptor complexes. There are four major members of the JAK family, all of which are composed of non-receptor tyrosine protein kinases. The STAT family contains six members which consist of 750–900 amino acids. The JAK/STAT signaling pathway is mainly thought to mediate inflammation, apoptosis, hematopoiesis, tissue repair, immune regulation, and adipogenesis [109]. In autoimmune diseases such as rheumatoid arthritis (RA), activation of the JAK-STAT signaling pathway leads to the progression of joint injury through overexpression of the matrix metalloproteinase gene, apoptosis of chondrocytes, and apoptotic resistance in synovial tissue [110,111]. In addition, in a 2020 study by Meyer LK, the inhibition of the JAK-STAT signaling pathway was found to sensitize CD8+ T cells to dexamethasone-induced excessive inflammatory cell apoptosis [112]. Song et al. have long discovered that the lifespan of NSCLC cells was notably reduced after inhibiting STAT3 [113]. In a murine lung model, overexpression of STAT3 in alveolar type II cells led to severe lung inflammation and eventually to the formation of LUAD [114]. Further, downregulation of STAT3 was found to result in enhanced NK cell immunity in both human and murine NSCLC cells, which suggests that STAT3 plays an inhibitory role against tumor NK cell immunity [115,116]. A study last year disclosed that IL-22 triggers JAK-STAT3 pathway phosphorylation in NSCLC cells in a time- and dose-dependent manner, thus promoting the proliferation and metastasis of tumor cells [23,96]. Another study demonstrated that the overexpression of IL-22 protected lung cancer cells against apoptosis induced by serum starvation and chemotherapy drugs by activating STAT3 and its downstream anti-apoptotic proteins [24].

4.3 p38 MAPK signaling pathway

The p38 mitogen-activated protein kinases (MAPK) signaling pathway takes a crucial role in signaling cascades induced by various cellular stimuli. There are four p38 kinase members in the mammalian mitogen-activated protein (MAP) family, which play momentous roles in extracellular stimulation-mediated proliferation, inflammation, differentiation, apoptosis, senescence, and tumorigenesis [117]. In the classical pathway, the p38 MAPK signaling pathway is activated by cascade phosphorylation [118]. In a hepatitis C virus (HCV) experiment, researchers demonstrated that virus-induced activation of the p38 MAPK signaling pathway promotes viral infection, and blocking activation of this pathway may be an antiviral approach [117]. According to Dan He in 2020, mTORC1 drives intestinal stem cell aging via the p38 MAPK-p53 signaling pathway [119]. The p38 MAPK signaling pathway has long been demonstrated to exhibit a major oncogenic role in LUAD [[120], [121], [122]]. Yinan Guo et al. found evidence that the p38 MAPK signaling pathway can promote EMT and metastasis of NSCLC both in vitro and in vivo [123]. In addition, a study published in 2017 proposed that the p38 MAPK signaling pathway activates stem cell properties of LUAD cells by regulating GLI1 [124]. What's more, in lung cancer models, researchers found that the p38 MAPK signaling pathway inhibited the stem cell properties of lung CSCs and promoted their proliferation and differentiation, thereby leading to tumorigenesis. More importantly, they also elucidated that the p38 MAPK and PI3K/AKT signaling pathways have unique and synergistic roles in regulating lung CSCs self-renewal as carcinogenic and/or stem cell signaling pathways [107]. This provides a new idea for the stem cell-based treatment of lung cancer. In NSCLC, IL-22 in vivo and in vitro were both verified to activate the p38 MAPK signaling pathway. The collected evidence from this study confirmed the negative immunomodulatory role of IL-22 in the disease [96].

5 Clinical role of IL-22 in lung cancer

Currently, there is still a lack of efficient biomarkers for the diagnosis and treatment of lung cancer. In recent years, the value of the interleukin family as biomarkers and therapeutic targets of lung cancer has been deeply investigated [[125], [126], [127], [128], [129], [130], [131], [132]]. Of these, IL-1 and IL-6 have been studied most extensively in lung cancer. Bo Yuan's findings in mice experiments supported IL-1β as a potential target for the prevention and treatment of LUAD patients with Kras mutations [129]. In a clinical trial of the anti-IL-1β antibody canakinumab, researchers found that 300 mg canakinumab significantly reduced lung cancer mortality compared with the control group (HR 0.49 [95%CI 0.31–0.75]; p = 0.0009) [133]. In plasma samples or tumor tissues from NSCLC, researchers revealed that patients with lower baseline IL-6 concentrations benefited more from immunotherapy. The study elucidated the role of IL-6 in predicting the efficacy of immunotherapy in patients with NSCLC [128]. Furthermore, in one lung cancer study, the survival hazard ratio before and after chemotherapy for high versus low IL-6 levels was 1.25 (95%CI 0.73–2.13) and 3.66 (95%CI 2.18–6.15), respectively. It is suggested that IL-6 maybe a prognostic indicator of survival in patients with advanced NSCLC receiving chemotherapy [127]. Some scholars have also described the potential value of IL-11 as a biomarker for the diagnosis and prognosis of NSCLC [125]. In addition, another research has shown that changes in serum IL-8 levels in NSCLC patients could reflect and predict the response to immunotherapy [130]. Kaplan-Meier survival analysis showed that the overall survival outcome of NSCLC patients with high IL-22R1 expression was significantly lower than that of patients with low IL-22R1 expression (p = 0.022). Multivariate regression analysis also confirmed an association between IL-22R1 levels and poorer outcomes (HR 1.5, 95%CI 1.2–1.9; p = 0.0011). This suggested that high expression of IL-22R1 is an independent factor for low overall survival in NSCLC [134]. What's more, the levels of IL-22-producing Th22 cells in peripheral blood were positively correlated with TNM stage, lymph node metastasis, and clinical tumor markers of lung cancer (p < 0.01) [96]. The above indicates the significance of IL-22 as a biomarker in the diagnosis and disease assessment of lung cancer. Apart from this, Renhua Guo's team found that the expression of IL-22 in the EGFR-TKI resistant group was higher than that in sensitive group in NSCLC, and the expression level was correlated with the efficacy of EGFR-TKI in plasma [135]. Therefore, it is reasonable to suspect that IL-22 may be a new biomarker to overcome EGFR-TKI resistance in NSCLC. In terms of animal models, some investigators implanted Line-1 lung cancer cells into wild-type and IL-22-deficient mice simultaneously, and found reduced intrapulmonary metastasis in the latter group, which is independent of primary tumor size. Besides, they performed forced metastasis by intravenous injection of lung cancer cells, and the results further confirmed the lower metastatic load in mice with IL-22 deletion [72]. In another model of Kras-mutated lung cancer in mice, gene ablation of IL-22 resulted in a marked reduction in tumor number and size. The authors also analyzed the association between IL-22R1 expression and survival in patients with KRAS mutant lung adenocarcinoma, the results showed that high expression of IL-22R1 was an independent indicator of poorer relapse-free survival [94]. Taken together, these pieces of evidence highlight the potential clinical role of IL-22, IL-22R, and IL-22-producing cells in the treatment of lung cancer (Table 2).

6 Future perspectives

6.1 CRISPR-Cas13a technical

At present, mounting clinical trials based on IL-22 are being carried out in full swing worldwide, mainly involving ulcerative colitis, alcoholic cirrhosis, GVHD, and psoriasis [12,14,54,60]. However, there are presently no clinical trials based on IL-22 in lung cancer. As described previously, reduced intrapulmonary metastasis was found in IL-22-deficient mice as well as in IL-22-suppressed NSCLC cells [20,72]. In addition, blocking IL-22R1 or knockout of the IL-22 gene both retarded the progression of lung cancer [24,94]. These findings provide a new train of thought for the down-regulation of IL-22 in treating lung cancer.

In recent years, the research on gene editing treatment for various diseases has become more and more popular [[136], [137], [138]]. CRISPR-Cas13a is an effective tool for knocking out specific RNA sequences, it has been shown to induce the death of glioma cells that overexpress EGFR, which is one of the subtypes of EGFR mutation in glioma. Apart from this, the CRISPR-Cas13a gene-editing system can also inhibit the formation of intracranial tumors in mice with glioma [139]. In a collagen-induced mouse model, injection of gene-edited human amniotic mesenchymal stem cells that overexpressed IL-10 increased proteoglycan expression in joint tissue and reduced the inflammatory response and production of various inflammatory cytokines [137]. In the world's first human phase I clinical trial utilizing CRISPR-Cas9 in the treatment of advanced NSCLC, researchers have demonstrated the feasibility and safety of gene-edited T-cell therapy targeting the PD-1 gene [140]. Thus, genome editing strategies have the potential to treat lung cancer by altering IL-22 expression levels. In the future, the role of pulmonary precision delivery based on CRISPR-Cas13 gene-editing components targeting the IL-22 mRNA in lung cancer therapy should not be ignored. CRISPR-Cas13 is expected to be further integrated with the latest technologies such as single-base editing and single-cell sequencing to promote the treatment of lung cancer to a new level (Fig. 4).Fig. 4 Crispr-cas13-based IL-22 mRNA editing can be utilized for lung cancer therapy by combining with emerging technologies such as single-base editing and single-cell sequencing.

Fig. 4

6.2 Small interfering RNA

Small interfering RNA (siRNA) is a double-stranded RNA molecule composed of 21–23 nucleotides. In cells, siRNA forms functional complexes by binding to the RNA-induced silencing complex (RISC). RISC in the functional complex specifically recognizes and binds to the target mRNA, leading to degradation of the target mRNA and thereby silencing the expression of the target gene. Compared with traditional therapies such as small molecules and protein drugs, siRNA technology has many advantages: 1) siRNA is highly specific. siRNA can only silence homologous genes, while unrelated genes are not affected. 2) siRNA can silence genes by using RISC. 3) siRNA can be designed to target different genes through sequence design, and can even target targets that were previously considered “undruggable”. 4) siRNA does not activate the innate immune system. Twenty years after the discovery of the RNA interference mechanism, the first siRNA drugs (including Patisiran, Givosiran, Lumasiran, Inclisiran, Vutrisiran) were approved for clinical use by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency from 2018 to 2022 [141,142]. NFKBIZ is an upstream target of IL-23, IL-36 and IL-17A. In the study of Mandal A et al. [143], NFKBIZ-siRNA significantly reduces the mRNA levels of multiple pro-inflammatory cytokines, including IL-17, IL-19, IL-22, etc., in the skin tissue of psoriasis mice, thereby alleviating the condition of the mice. The safety evaluation results of NFKBIZ-siRNA preparations show that NFKBIZ-siRNA preparations can complex with nucleic acids without affecting biological activity and show no toxicity. TGF-β is a pleiotropic regulatory cytokine that can regulate a variety of ILs including IL-22 and IL-17 to affect the composition of the tumor microenvironment [144]. Currently, Sirnaomics has developed an siRNA drug that targets TGF-β (called STP705). Recently, the drug has completed phase II clinical trials in the United States and achieved positive results. The role of ILs in cancer has been extensively studied. In recent years, the positive role of IL-22 in lung cancer has received attention. The researchers believe that knocking down IL-22mRNA levels in the lesions of lung cancer patients will help prolong the survival of lung cancer patients and improve the cure rate of lung cancer patients. For example, Zhang Wei et al. found that IL-22-siRNA slowed tumor growth in NSCLC model mice. In addition, they reported that the therapeutic effect of IL-22-siRNA combined with chemotherapy drugs (5-FU and carboplatin) on NSCLC mice was better than that of chemotherapy drugs alone [24]. In an in vitro assay [145], cell line PC9 cells (NSCLC) transfected with PDLIM5-siRNA targeting the PDLIM5 gene had reduced growth viability and exhibited higher apoptotic rates. In the chemotherapy drug gefitinib-resistant cell line PC9 cells, PDLIM5-siRNA still showed significant anti-tumor effects. These results indicate that siRNA-based therapy has good application in the clinical treatment of NSCLC, especially in drug-resistant patients. Based on these findings, we believe that the development of IL-22-siRNA drugs for lung cancer treatment has clinical potential and theoretical basis.

6.3 Nanoparticle drug delivery systems

On the other hand, given the toxicity and erratic efficacy of current anti-tumor drugs, research on novel drug carriers in lung cancer is also of vital significance. Nanoparticles containing targeted drugs can be delivered to the intended site using carriers with affinity for various specific tissues or lesions [146,147]. In an in vivo mice lung model, combined delivery of sorafenib and crizotinib by polymer nanoparticles significantly reduced tumor progression and toxic side effects, and improved survival rate [148]. Moreover, Maofan Zhang demonstrated that the efficacy of dual-drug-loaded polymeric nanoparticles with etoposide and cisplatin was significantly superior to conventional chemotherapy modality without causing additional toxicity [149]. These imply that nanomaterials loaded with IL-22-related drugs may also have more unique advantages. Therefore, the utilization of novel nanomaterials loaded with IL-22 antibodies and IL-22 inhibitors like IL-22BP for targeted therapy of lung tumors is also a promising research direction (Fig. 5).Fig. 5 Precision delivery of various nanomaterials containing IL-22 related drugs for the treatment of lung cancer.

Fig. 5

7 Conclusion

In this review, we provided a comprehensive analysis of the role of IL-22 in the immune microenvironment and its involvement in major signaling pathways in the context of lung cancer. Put in a nutshell, IL-22 not only antagonizes the induction of apoptosis and cell cycle arrest of lung cancer cells by anti-tumor drugs but also promotes the proliferation and metastasis of lung cancer cells and the growth of tumor tissues. Additionally, the potential clinical significance of IL-22 in the diagnosis, treatment, and prognosis evaluation of lung cancer was further confirmed. Next, the prospects of IL-22 in combination with gene editing and novel nanomaterials in the treatment of lung cancer have been discussed. With the general increase in drug resistance to chemotherapy, targeted therapy, and immunotherapy in lung cancer, it is also necessary to study in depth to discover the correlation between IL-22 and the mechanism of drug resistance. To sum up, the potential of IL-22 as a biomarker for lung cancer still remains to be explored. Further research on the molecular, physiological effects and mechanism of IL-22 in lung cancer as well as the conduction of standardized clinical trials are expected to inject fresh blood into the diagnosis and treatment of lung cancer.

Financial support

None.

Data availability statement

Not applicable.

CRediT authorship contribution statement

Ling Xu: Writing – original draft. Peng Cao: Visualization. Jianpeng Wang: Writing – review & editing. Peng Zhang: Validation. Shuhui Hu: Validation. Chao Cheng: Writing – review & editing. Hua Wang: Writing – review & editing, Supervision, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

non-small cell lung cancer NSCLC

Interleukin-22 IL-22

chimeric antigen receptor CAR

IL-10-related T cell-derived inducible factor IL-10-TIF

Group 3 innate lymphoid cells ILC3

IL -22 receptor IL-22R

aryl hydrocarbon receptors AhR

chronic obstructive pulmonary disease COPD

cutaneous T-cell lymphoma CTCL

bronchoalveolar lavage fluid BALF

receptor tyrosine kinases RTKs

G-protein-coupled receptors GPCRs

Mammalian target of rapamycin mTOR

idiopathic pulmonary fibrosis IPF

rheumatoid arthritis RA

mitogen-activated protein kinases MAPK

mitogen-activated protein MAP

hepatitis C virus HCV

Acknowledgements

None.
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