Published online Jun 24, 2026. doi: 10.5306/wjco.121169
Revised: April 8, 2026
Accepted: May 6, 2026
Published online: June 24, 2026
Processing time: 96 Days and 23.1 Hours
Lung cancer is characterized by the uncontrolled proliferation of abnormal cells in one or both lungs, typically originating from the epithelial lining of the airways. Cytokines are small, biologically active proteins that function as signaling mo
Core Tip: Numerous tumor markers and cytokines have been identified and investigated in relation to lung cancer development and progression. However, we focused on carcinoembryonic antigen, squamous cell carcinoma, cytokeratin 19 fragment, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1 and neuron-specific enolase in the pathogenesis of lung cancer.
- Citation: Tariq M, Sattar A, Khalid A, Azam M, Mehmood M, Hafeez R, Rafaqat S. Role of tumor markers and cytokines in the pathogenesis of lung cancer. World J Clin Oncol 2026; 17(6): 121169
- URL: https://www.wjgnet.com/2218-4333/full/v17/i6/121169.htm
- DOI: https://dx.doi.org/10.5306/wjco.121169
Lung cancer is characterized by the uncontrolled proliferation of abnormal cells in one or both lungs, typically originating from the epithelial lining of the airways. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of instances of lung cancer, which is a significant cause of cancer-related mortality worldwide[1]. The most prevalent kind of bronchial malignancy is called NSCLC. They are frequently divided into two primary histological groups: Adenocarcinoma and squamous cell carcinoma (SCC). DNA copy number, DNA methylation, gene mutations, transcriptome, proteome, and possible biomarkers are all different in adenocarcinoma and squamous carcinoma cells[2]. Unfortunately, many patients receive a diagnosis of advanced-stage lung cancer, which restricts their options for treatment to palliative chemotherapy. As a result, the majority of patients have a life expectancy of one to two years[3]. Innovative therapy techniques are essential for improving treatment results and extending survival in patients with advanced NSCLC.
Cytokines are small, biologically active proteins that function as signaling molecules, mediating communication between cells and regulating immune and inflammatory responses. In the context of lung cancer, cytokines play a crucial role in modulating the tumor microenvironment (TME) and influencing immune responses against malignant cells. Tumor markers and inflammatory cytokines are key contributors to the pathogenesis of lung cancer, facilitating tumor initiation, angiogenesis, and disease progression within an inflammatory microenvironment. Furthermore, they promote immune evasion, epithelial-mesenchymal transition, and metastatic dissemination, thereby serving as important diagnostic, prognostic, and therapeutic targets[4].
For patients with NSCLC undergoing chemotherapy in addition to PD-1 inhibitor treatment, serum cytokines, particularly interleukin (IL)-6, IL-5, IL-8, tumor necrosis factor (TNF)-α, IL-10, and IL-4, may be predictive variables[5]. The lack of validated blood tumor markers, which might aid in detection and perhaps spare the patient unnecessary interventional diagnostic procedures, is arguably one of the most significant unresolved difficulties in lung cancer. When associated with the disease’s clinical outcome, serum tumor markers can also have a predictive role. Additionally, it might bring in a new age of drugable targets, potentially improving the prognosis for advanced lung cancer. Numerous studies have examined the use of tumor markers in lung cancer, mostly for staging, post-therapeutic follow-up, prognosis assessment, and even early diagnosis[6].
Zhang et al[7] offers important insights into the diagnostic utility of tumor markers and cytokines in lung cancer. In their study, Zhang et al[7] investigated the diagnostic performance of conventional tumor markers in combination with inflammatory cytokines for the detection of lung cancer and developed a multiparameter diagnostic model to improve early identification of the disease. Specifically, the authors evaluated the diagnostic significance of ten cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, IL-10, IL-1β, IL-2, IL-4, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and TNF-α. Furthermore, the study assessed both the diagnostic value of individual biomarkers and their combined diagnostic performance. Based on these analyses, Zhang et al[7] constructed an integrated biomarker-based diagnostic model to enhance the screening and early detection of lung cancer.
Numerous tumor markers and cytokines have been identified and extensively investigated for their roles in the development and progression of lung cancer[8]. However, in the present editorial, we specifically focused on selected biomarkers, including carcinoembryonic antigen (CEA), SCC antigen, cytokeratin 19 fragment, TNF-α, GM-CSF, IFN-γ, and several ILs such as IL-1, IL-2, IL-4, IL-6, IL-8, and IL-10, along with MCP-1 and neuron-specific enolase (NSE). These biomarkers were examined in the context of their involvement in the pathogenesis of lung cancer. In addition, we highlighted their potential clinical implications, particularly regarding their diagnostic, prognostic, and therapeutic relevance in the management of lung cancer. Table 1 explains the circulating levels of tumor markers and cytokines associated with the pathogenesis of lung cancer. Table 2 shows the overall summary of tumor markers and cytokines in the pathogenesis of lung cancer.
| Tumor markers and cytokines | Circulating levels |
| CEA | Increased level |
| SCC | Not yet reported |
| CK19 | Increased level |
| TNF-α | Increased level |
| GM-CSF | Increased level |
| IFN-γ | Increased level |
| IL-1 | Increased level |
| IL-2 | Increased level |
| IL-4 | Increased level |
| IL-6 | Increased level |
| IL-8 | Increased level |
| IL-10 | Increased level |
| MCP-1 | Increased level |
| NSE | Increased level |
| Tumor markers and cytokines | Pathogenesis in lung cancer |
| TNF-α | In lung cancer, TNF-α contributes to tumor initiation, progression, and metastasis |
| TNF is a major factor in non-small cell lung cancer caused by inflammation, angiogenesis, and metastasis | |
| IFN-γ | Modulates the TME and is negatively correlated with the expression of immune metagenes |
| Causing apoptosis in the lung cancer cells and restoring RNase L function | |
| IFN-γ-enhanced CD47 expression is a unique mechanism that promotes the development of human lung adenocarcinoma | |
| IL-1 | IL-1β binds to this receptor and initiates signaling pathways, such as the MAPK, cyclooxygenase, and NF-κB pathways, which result in the activation of macrophages, the intratumoral accumulation of immunosuppressive myeloid cells, and the growth, invasiveness, metastasis, and angiogenesis of tumors |
| Tumor-cell motility and invasion are promoted by promoting glycolysis of LUAD cells through p38 signaling | |
| IL-2 | IL-2 expression was substantially positively connected with several immune cells, such as B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells |
| IL-4 | The Th2 cytokine IL-4 increased macrophage-dependent tumor cell extravasation |
| IL-6 | IL-6/STAT3 signaling stimulated the growth of lung cancer cells by inducing the cell proliferation regulator cyclin D1 |
| The development of depression and lung cancer may be related to the up-regulation of indoleamine 2,3-dioxygenase brought on by IL-6 | |
| Tumorigenesis and metastasis | |
| IL-8 | Tumor-promoting characteristics |
| Increased cell proliferation | |
| CXCR1 receptor primarily mediates the mitogenic action of IL-8 in lung cancer, and it can operate as an autocrine and/or paracrine growth factor for lung cancer cells | |
| Angiogenesis and lung cancer spread | |
| IL-8 causes non-small cell lung cancer cells to proliferate by transactivating the epidermal growth factor receptor | |
| IL-8 increases epithelial cell proliferation | |
| IL-10 | A multifunctional cytokine with immunosuppressive and anti-angiogenic qualities, IL-10 is crucial to the pathophysiology of cancer |
| The regulation of tumor development and metastasis may be significantly influenced by IL-10 | |
| Development of lung cancer | |
| Both IL-10 and IL-10R were shown to be elevated in the cells surrounding the lung tumor cells, and IL-10R was mostly expressed on the surface of Foxp-3+ T-regulatory lymphocytes infiltrating the patients' tumors, where its expression was negatively linked with programmed cell death 1 | |
| IL-6 and TNF-α | IL-6 and TNF-α levels were positively correlated with distant metastasis and lymph node metastasis |
| They were negatively correlated with E-cadherin levels and positively correlated with N-cadherin and vimentin levels | |
| To sum up, IL-6 and TNF-α can cause the epithelial-mesenchymal transition, which in turn can encourage lung cancer spread |
The extracellular domain of CEA, which belongs to the glycosylphosphatidylinositol (GPI)-linked immunoglobulin superfamily, is anchored to the cell membrane by GPI anchors[9]. CEA has other biological functions in addition to being used as a tumor marker. Intercellular adhesion, regulatory signal transmission, cell proliferation, differentiation, apoptosis, angiogenesis, and immunological response are some of these roles[10].
The CEA increases were primarily found in interstitial lung disease patients, pneumonitis, and chronic obstructive pulmonary disease (COPD), and have a strong correlation with patient age. Pulmonary alveolar proteinosis exhibited the greatest positive rate of CEA increases, whereas pulmonary tuberculosis had the lowest. Most individuals with unusually high CEA levels have many underlying conditions, namely endocrine disorders, circulatory system disorders, and heart or respiratory failure. Patients with endocrine problems had diabetes. Patients with benign lung diseases have a modest positive incidence of CEA in their serum, but very few have levels higher than 20 ng/mL[11].
It is yet unknown how CEA functions as a blood biomarker in lung cancer. To ascertain its usefulness in tumor response assessment as an adjuvant to scans in advanced cancer, another study assessed pre-systemic anti-cancer therapy CEA levels, correlations with elevated CEA, and concordance between change in CEA and radiological response. 68% of the 100 individuals had an elevated baseline CEA. COPD was a major risk factor, with a tendency towards elevated levels in men, age ≥ 65 years, tobacco smoking in the past or present, metastases to the liver and/or pancreas, and the brain. Absolute CEA levels were greater in patients with pancreatic and/or liver metastases[12].
Tumor cells are the main source of CEA, which a tumor-associated antigen. Many biological processes, including cell adhesion, proliferation, differentiation, and metastasis, have been linked to it. Nevertheless, it is still mostly unknown what specific molecular processes CEA uses to promote tumor cell growth. CEA inhibits cisplatin-induced apoptosis in NSCLC cells while simultaneously promoting NSCLC proliferation and migration. In A549 and H1299 cells, treatment with CEA increased the number of mitochondria and caused lipid droplets to accumulate. Furthermore, CEA is involved in controlling NSCLC cells’ fatty acid metabolism. The CEA-mediated migration and proliferation of NSCLC cells were considerably decreased by blocking fatty acid metabolism[13].
By triggering the peroxisome PGC-1α signaling pathway, CEA affects fatty acid metabolism and NSCLC cell growth. Through this regulatory mechanism, CEA raises intracellular cyclic adenosine monophosphate levels, activating PKA and upregulating PGC-1α. Both in vitro and in vivo, blocking the PKA-PGC-1α signaling pathway in NSCLC decreases fatty acid metabolism as well as the proliferation and migration brought on by CEA. These findings imply that CEA modulates fatty acid metabolism, which in turn promotes migration and proliferation[14].
Both malignant pleural effusion and serum CEA levels are elevated in lung cancer. Nevertheless, it has not been reported that a CEA rise occurs in cytologically negative pleural effusion when adenocarcinoma is present without pleural infiltrate. Here, a study described the case of an 82-year-old man who, despite null cytological results, had incidental early-stage adenocarcinoma of the right upper lobe and had elevated CEA in blood and pleural fluid[15].
The tumor was removed by wide wedge resection due to low lung reserve; nevertheless, pleural biopsies ruled out invasion of the parietal pleura, and the visceral pleura was unaffected. Following surgery, serum and pleural CEA levels decreased during the one- and two-month follow-up. In this instance of early-stage lung adenocarcinoma (LUAD) with negative cytology and no evidence of pleural infiltration, there is an increase in CEA in the serum and pleural fluid. The amount of CEA in pleural effusion is correlated with blood CEA and is much greater in LUAD as compared to other types of lung cancer[16].
SCC antigen is a glycoprotein biomarker that is specifically associated with lung SCC and accounts for approximately 30% of NSCLC cases. SCC antigen is secreted by malignant squamous epithelial cells and reflects the proliferation and invasion of tumor cells[15]. Lung squamous-cell carcinomas are characterized by distinct clinicopathological and molecular features that have changed significantly over time. In the past, these tumors were thought to be central tumors with great molecular complexity and no detectable genetic alterations, and they were the most prevalent subtype of non-small-cell lung malignancies[16].
A novel cytokeratin 19 fragment called CK19-2G2 may serve as a tumor marker for lung cancer diagnosis. Although there is currently no standard serum tumor marker for lung cancer, high serum concentrations of cytokeratin 19 fragment (CYFRA 21-1) are mostly associated with tumor load and suggest a poor prognosis[17,18]. The 90% of lung cancer patients had high CK19, compared to 7% of controls. All of the progressive disease patients had high CK19. Overall survival (OS) at one year was 61% in high CK and 33% in normal CK[6].
Serum levels of the cytokeratin 19 fragment have previously been shown to be an effective tumor marker for lung cancer. Fujita et al[19] postulated that individuals with radiation pneumonitis would have elevated levels of CYFRA 21-1 due to damage to their epithelial cells.
Patients with diffuse radiation pneumonitis had substantially higher levels of CYFRA 21-1 in their sera than either normal smokers or patients with local radiation pneumonitis. As diffuse radiation pneumonitis progressed or improved, CYFRA 21-1 levels in serum altered accordingly. Using pulmonary tissues from autopsied individuals with radiation pneumonitis, an immunohistochemistry investigation revealed that the anti-human cytokeratin 19 antibody highly stained the hyaline membrane and proliferating type II pneumocytes. The individuals with diffuse radiation pneumonitis had higher levels of CYFRA 21-1[19].
In 64 patients with non-small cell N2M0 lung cancer, in relation to cytokeratin 19 fragment levels were examined in connection with the T factor. There was no difference in the levels of T3 and T4, despite a connection between the levels and the T factor. The groups with limited tumors (T1 + T2: n = 28), those with tumors expanding to the pleura or chest wall (T3: n = 13), and those with tumors penetrating the mediastinum (T4: n = 12) also had increases in serum CYFRA 21-1 levels. The group with malignant pleural effusion (T4: n = 11) had a lower level than the group with mediastinum-invading tumors. The three-dimensional growth of the tumor is unrelated to the occurrence of malignant pleural effusion, which explains why CYFRA 21-1 levels in T4 are not greater than those in T3[20].
Patients with lung cancer had considerably greater preoperative baseline serum CK19-2G2 (a new fragment of cytokeratin 19) levels than both healthy controls and patients with benign illnesses. Within a week following tumor removal, the postoperative levels of CK19-2G2 dramatically decreased. After that, the patients who had palliative procedures had a further decline, whereas the CK19-2G2 levels of the patients in the radical resection group stabilized[21].
The level of CYFRA 21-1 was associated with the positivity of the competitive reverse transcriptase-PCR for caspase 3 and immunohistochemistry for caspase 3 in five cell lines that generated a notable quantity of the protein. This suggests that caspase 3 played a role in the formation of CYFRA 21-1. The release of CYFRA 21-1 in culture supernatants was considerably suppressed by the particular caspase 3 inhibitor. Dohmoto et al[22] showed that the production of CYFRA 21-1 in human lung cancer cell lines was significantly influenced by caspase 3, which cleaves several intermediate filaments and initiates cell death.
TNF-α can connect to two different receptors (TNFR1/2). TNFR2 is preferentially bound by the transmembrane form (tmTNF-α). TACE cleaves tmTNF-α, releasing its soluble form (sTNF-α), which has a greater affinity for TNFR1. This combination gives TNF-α a variety of conflicting functions in angiogenesis, metastasis, tumor cell survival (and death), and anti-tumor immune activation (and repression)[23].
In NSCLC, TNF and its receptors are abundantly expressed. In addition to its well-established function in inflammation, TNF is a major factor in cancer caused by inflammation. Nonetheless, TNF is probably carcinogenic in several cancer forms, including NSCLC[24].
The gene expression patterns of two separate murine models of TNF-α/TNFR KO were examined. The most prominent route linked to genes regulated by TNF-α was the epidermal growth factor receptor signaling pathway. Wang et al[25] evaluated the expression patterns of the TNF-α-mediated genes in human lung tissues collected from tumors and normal tissues after matching the TNF-α-mediated mouse genes to their human orthologs.
By directly regulating COX-2 expression, independent of an autocrine mechanism, G-CSF and GM-CSF might accelerate the growth of tumors[26]. GM-CSF is produced in large quantities by bronchial epithelial cells and is thought to mediate both inflammation and host defense. Many tumor cells generate GM-CSF, which is also linked to tumor development and metastasis. The physiologic function of GM-CSF generated by squamous cell lung cancer was examined. The in vitro invasiveness and matrix metalloproteinase activity of SCC cell lines were directly correlated with their production of GM-CSF. In a dose-dependent fashion, recombinant GM-CSF increased the invasiveness of less invasive LK-2 and LC-1 cells; the neutralizing anti-GM-CSF antibody reversed this stimulation[27].
Additionally, highly invasive EBC-1 and NCI-H157 cells were less invasive when exposed to anti-GM-CSF antibody. Additionally, GM-CSF enhanced LK-2 and LC-1 cell matrix metalloproteinase activity. Of the 113 non-small cell lung carcinomas that were removed, 24 of 42 adenocarcinomas (57.1%) and 30 of 71 SCCs (42.3%) had positive GM-CSF staining. In SCCs, GM-CSF expression was linked to the initial tumor’s local invasion. These findings imply that GM-CSF synthesis has a role in both the local advancement of lung SCC and its in vitro invasiveness[27].
The intricate process of tumor immune evasion encompasses a number of processes, including immune system inhibition, T cell depletion, and antigen recognition limitation. Numerous immunological cells implicated in immune evasion can be seen in the TME. Granulocyte colony-stimulating factor and GM-CSF have been shown in recent research to modulate neutrophils and myeloid-derived suppressor cells to cause immune evasion in lung cancer. Here, another study[28] discusses the genesis and roles of G-CSF and GM-CSF, with a focus on their function in lung cancer immune evasion[28]. Lastly, Kowanetz et al[29] reported that the administration of recombinant G-CSF is adequate to boost the quantity of Ly6G+Ly6C+ cells at organ-specific metastatic sites and enhances the capacity of several cancers to metastasize.
IFN-γ drives apCAFs growth through the JAK1/2-STAT1-IFI6/27 pathway using a proprietary biobank of cancer-associated fibroblasts. Mechanistically, apCAFs play a major role in PD-L2 expression in the TME, which in turn causes FOXP1+ regulatory T cells (Tregs) to proliferate via the PD-L2-RGMB axis. Reprogramming apCAFs by blocking the PD-L2-RGMB axis or suppressing the IFN-γ pathway significantly reduces the growth of FOXP1+ Tregs caused by apCAFs[30].
Lung cancer may have different immunoregulation mechanisms than other cancers, as the lung is a mucosal barrier organ with a distinct immunologic milieu. In line with this theory, it was discovered that CD8+ T cells paradoxically contributed to the development of many lung cancer models rather than slowing it down. These included models of tumor cell lines that were transplantable, carcinogen-induced, and spontaneous. In particular, CD8+ T cells enhanced the homing of CD4+ Foxp3+ Tregs to the tumor bed by raising CCR5 chemokine levels in the TME in a TNF-α and IFN-γ-dependent manner. These Th1 cytokines, in contrast to their classical function, suppressed the growth of other cancers while accelerating the growth of murine LUADs. Remarkably, lung cancer cells themselves can be a major source of IFN-γ, and CRISPR/Cas9 deletion of this cytokine from cancer cells slows the development of tumors. Significantly for translational applications, both mRNA and protein levels of IFN-γ were shown to be elevated in lung cancer patients[31].
IFN-mediated antiviral signaling, which has demonstrated antitumor effects in cancer, depends on RNase L. When IFN-γ was applied to lung cancer cells, RNase L expression increased, compensating for the suppression of RLI (RNase L inhibitor) and restoring RNase L’s cytoplasmic and nuclear functions, which caused the cells to undergo apoptosis. Therefore, Yin et al[32] identified the mechanism and decreased function of RNase L in lung cancer cells and demonstrated the effectiveness of IFN-γ in causing apoptosis in the lung cancer cells and restoring RNase L function.
During the development of LUAD, IFN-γ modulates the TME in an involved manner. The high-risk group has a high concentration of pro-tumor immune cells and is enriched with genes controlling DNA replication and the cell cycle. Furthermore, the risk score has a positive correlation with genes that repair DNA damage but a negative correlation with the expression of immune metagenes[33].
By upregulating the self-marker CD47, tumor cells can avoid phagocyte assault. However, the processes behind the increase of CD47 in tumors are yet unknown. Here, another study found that IFN-γ, which is significantly elevated in the TME following tumor spread and treatment, upregulates human LUAD CD47. Regardless of CD47 protein expression, the IFN-γ receptor is expressed in a variety of human LUAD tissues, and lung cancer CD47 expression is markedly increased after tumor spread or chemotherapy. Accordingly, IFN-γ therapy significantly increases CD47 expression in different lung cancer cells. By activating IRF-1, which binds to an IRF-1-binding domain within the CD47 promoter region and stimulates CD47 transcription, IFN-γ mechanistically raises CD47 expression. Functionally, IFN-γ-induced CD47 upregulation and cancer metastasis are inhibited by altering the IRF-1-binding region within the CD47 promoter, whereas IFN-γ-enhanced CD47 expression promotes human lung cancer cell invasion both in vitro and in vivo. IFN-γ-enhanced CD47 expression is a unique mechanism that promotes the development of human LUAD[34].
A large portion of inflammation is produced by multicomplex cytosolic proteins called inflammasomes, which also activate the cytokine IL-1β. When a particular inflammasome, nucleotide-binding domain-like receptor protein 3, cleaves pro-IL-1β into its active form, IL-1β is activated. Lung cancer is associated with an up-regulation of nucleotide-binding domain-like receptor protein 3. IL-1β binds to this receptor and initiates signaling pathways, such as the MAPK, cyclooxygenase, and NF-κB pathways, which result in the activation of macrophages, the intratumoral accumulation of immunosuppressive myeloid cells, and the growth, invasiveness, metastasis, and angiogenesis of tumors[35].
Tumors, glycolysis, and inflammation are all closely related. Important inflammatory cytokines belong to the IL-1 family, among which IL-1β has been extensively researched. Tan et al[36] investigated the potential mechanisms behind the impact of IL-1β on the glycolysis of LUAD cells both in vitro and in vivo. The expression of glycolysis-related enzyme genes in LUAD was positively linked with IL-1β. When A549 and LLC were activated with IL-1β, glycolysis, migration, and invasion were dramatically enhanced. The glycolysis inhibitor 2-deoxy-D-glucose and p38-pathway inhibitors prevented IL-1β from promoting growth, mean standard uptake value, and pulmonary tumor metastasis in vivo. ZINC14610053, a small molecule, has been proposed as a possible inhibitor of IL-1β, which further enhances tumor-cell motility and invasion by promoting glycolysis of LUAD cells through p38 signaling[36].
As Yano et al[37] previously documented, in NSCLC, the amount of serum sIL-2R increases as the disease progresses. Subsequent analyses showed that in seven out of sixteen instances of LUAD, tumor cells expressed IL-2Rα (CD25). These findings suggested that in certain cases of LUAD, the tumor cells did express IL-2Rα and produce sIL-2R.
IL-2 expression was reduced in LUAD patients compared to the normal control group. Additionally, the OS of individuals with low IL-2 expression was poor. Additionally, in patients with LUAD, IL-2 expression was substantially positively connected with a number of immune cells, such as B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Furthermore, there was a strong positive correlation between IL-2 expression and the immune cells. Additionally, PD-1, PD-L1, and CTLA-4 expression were positively linked with IL-2 expression[38].
Cancer cell extravasation, survival, and proliferation are facilitated in mice models of lung metastases by the migration of classical monocytes from blood to the lung and their transformation into metastasis-associated macrophages (MAMs). Metastasis is prevented when MAMs or their monocytic progenitors are ablated. Another study investigated that tumor cell extravasation in the lung is influenced by variables that regulate macrophage polarization[39].
The impact of Th1 or Th2 cytokine signaling in macrophages on tumor cell trans-endothelial migration in vitro was assessed. The Th2 cytokine IL-4 increased macrophage-dependent tumor cell extravasation, but IFN-γ and LPS prevented it. IL4rα null mice develop fewer and smaller lung metastases. This phenotype was restored in IL4rα-deficient animals by adoptive transfer of wild-type monocytes. In vitro IL-4-mediated tumor cell extravasation requires the expression of the chemokine receptor CXCR2, which is regulated by IL-4 signaling in macrophages. Additionally, IL-4 signaling in macrophages transcriptionally controls several additional genes, such as CCL2 (also known as MCP-1), CSF1 (also known as M-CSF), CCR1, HGF (also known as SF), and FLT1 (also known as VEGFR-1), that are already causally linked to lung metastasis[39].
High-resolution intravital imaging of the lung in mice at the time of metastatic seeding validated the major function of IL-4 signaling in MAMs by demonstrating decreased physical contact between tumor cells and IL-4rα-deficient macrophages. Tumor cell survival is increased by this interaction. According to these findings, pro-tumoral paracrine transmission between cancer cells and macrophages is regulated by IL-4 signaling in monocytes and macrophages, which is crucial for the initiation and development of breast metastases in the lung[39].
Here, Qu et al[40] showed that in a mouse model of lung cancer caused by the K-Ras oncogene, IL-6 has opposing functions in the development and spread of lung cancer. Qu et al[40] discovered that after an activating mutant of K-Ras was generated in the lungs, IL-6-deficient mice developed many more lung tumors than wild-type mice. On the other hand, IL-6-deficient animals had much smaller lung tumors. Notably, IL-6’s capacity to activate the transcription factor STAT3 under K-Ras oncogenic stress suppressed the initiation of lung cancer by maintaining lung homeostasis, controlling lung macrophages, and activating cytotoxic CD8 T cells. On the other hand, IL-6/STAT3 signaling stimulated the growth of lung cancer cells by inducing the cell proliferation regulator cyclin D1[40].
Patients with lung cancer are more likely to have depression, and depression is frequently linked to a poor prognosis for lung cancer. One of the variables in the presumed aetiology of depression is an excessive inflammatory response, and the inflammatory milieu is also important in the development of tumors, which may point to a shared factor between the brain and the lung. Since critical pulmonary conditions, including acute lung damage and acute respiratory distress syndrome, seem to be the source of mood problems and poor cognitive results, a novel theory known as the lung-brain axis has recently been put forth. Thus, the lung-brain axis may have an impact on depression and lung cancer[41].
The IL-6 pathway can stimulate glial M1 and A1 phenotypic activity, which in turn activates indoleamine 2,3-dioxygenase (IDO), which reduces the production of 5-hydroxytryptamine (5-HT) and depletes tryptophan. Through the IL-6-JAK/STAT signaling pathway, IL-6 stimulation can also suppress the expression of the 5-HT transporter. Major neuropathological features of depression include these alterations. Since elevated IDO suppresses T cell growth and triggers lymphocyte death, the route might also contribute to lung cancer. Thus, the development of depression and lung cancer may be related to the upregulation of IDO brought on by IL-6[41].
Santoso et al[42] findings demonstrated that broader metastases occurred with greater serum COX-2 and IL-6 levels. In comparison to low COX-2 and IL-6 levels, the hazard ratios for lung cancer-specific survival for all patients were 1.59 (95%CI: 0.74-3.41) and 1.21 (95%CI: 0.57-2.54; P > 0.05). Although high levels of COX-2 and IL-6 were shown to be statistically significant with stages and metastasis, they were not associated with survival[42]. It was unknown how much IL-6, a crucial cytokine in inflammation, was expressed in individuals with advanced lung cancer. Greater levels of IL-6 were linked to a greater risk of progressive disease[43].
IL-8/CXCL8 is an angiogenic factor and chemokine. IL-8 has been found to be an autocrine growth factor in a number of human malignancies. Here, Zhu et al[44] looked at how lung cancer cells produce and use IL-8. A panel of NSCLC and small cell lung cancer (SCLC) cell lines were used to assess the expression of IL-8 and its receptors, including CXCR1 and CXCR2. Zhu et al[44] discovered that all NSCLC cell lines examined generated moderate to high amounts of IL-8 (up to 51 ng/mL/106 cells). On the other hand, SCLC cell lines expressed CXCR1 and CXCR2 but generated very little or no IL-8. Next, two NSCLC cell lines (H460 and MOR/P) that expressed both IL-8 and its receptors to see if IL-8 may function as an autocrine growth factor. Authors discovered that anti-IL-8 neutralizing antibody reduced cell growth to 71% and 76% in MOR/P and H460, respectively[44].
In four SCLC cell lines studied, exogenous IL-8 dramatically increased cell proliferation in a dose-dependent manner. The increase in cell proliferation ranged from 18% (P < 0.05) to 37% (P < 0.05). Analysis of proliferating cell nuclear antigen expression and cell cycle in H69 cells further showed that IL-8 stimulates cell proliferation. Additionally, it looked at the receptor or receptors that mediated IL-8's mitogenic effect in lung cancer cells. anti-CXCR1 antibody greatly decreased cell growth, whereas anti-CXCR2 antibody did not. In conclusion, the CXCR1 receptor primarily mediates the mitogenic action of IL-8 in lung cancer, and it can operate as an autocrine and/or paracrine growth factor for lung cancer cells[44]. Nevertheless, it is unclear which signaling mechanisms cause NSCLC to produce IL-8. Here, Favaro et al[45] demonstrated that TRAIL death receptors independently control IL-8 expression and release in several squamous and adenocarcinoma NSCLC cell lines.
NSCLC constitutively produce IL-8, which may be further increased by TRAIL or TNF-α therapy or by stopping glucose. NF-κB and MEK/ERK MAP kinases were required for both constitutive and inducible IL-8 production in A549 cells, and constitutive and glucose deprivation-induced IL-8 secretion involved DR4 and DR5, which are recognised regulators of these signaling pathways. These receptors were mostly found inside cells. DR4 and DR5 both controlled the ERK-MAPK and Akt (protein kinase B) pathways, but DR4 signaled via the NF-κB pathway[45].
IL-8 was additionally controlled by FADD, caspase-8, RIPK1, and TRADD. TRAIL, DR4, and DR5 expression levels were linked with IL-8 transcripts, according to analysis of patient mRNA expression data. Additionally, in lung squamous carcinoma and adenocarcinoma, TRAIL receptor expression levels were linked with indicators of angiogenesis and neutrophil infiltration. All of these findings point to TRAIL receptor signaling as a factor in the pro-tumorigenic inflammatory profile linked to NSCLC[45]. Lung cancer susceptibility has been linked to IL-8 rs4073 genotypes, particularly in smokers[46].
A cytokine of the CXC chemokine family, IL-8, has a role in neutrophil activation and recruitment. Furthermore, angiogenesis and lung cancer metastasis are only two of the many additional processes with which IL-8 has been linked. Cells from LUAD and muco-epidermoid carcinoma express both CXCR1 and CXCR2 IL-8 receptors and generate significant levels of IL-8. IL-8 promotes the development of NSCLC cells via transactivating the epidermal growth factor receptor (EGFR) receptor. EGFR has been linked to lung cancer because it is essential for controlling cell growth. MAPK activation is one of the downstream signaling processes that may be triggered by both EGFR ligands and receptor transactivation. Luppi et al[47] demonstrated that ligands of different GPCRs cause transactivation of the EGFR, which entails the release of membrane-bound EGFR ligands via metalloproteinase. Luppi et al[47] examined the impact of IL-8 on LUAD and muco-epidermoid carcinoma cell proliferation and to understand the mechanisms behind this proliferation in two distinct NSCLC cell lines (A549 and NCI-H292).
IL-8 increases epithelial cell proliferation in both NSCLC cell lines in a dose-dependent manner. A panmetalloproteinase inhibitor, an EGFR tyrosine kinase inhibitor, and a particular anti-EGFR blocking antibody all prevented IL-8 from promoting cell growth. The GPCR inhibitor pertussis toxin had comparable outcomes. While a p38 MAPK inhibitor did not affect IL-8-induced cell proliferation, inhibition of the MAPK p42/44 (ERK1/2) also prevented the mitogenic action of IL-8. Luppi et al’s findings[47] imply that metalloproteinase activity is involved in the transactivation of EGFR, which is how IL-8 promotes cell proliferation in NSCLC cell lines.
It is still debatable how IL-10 contributes to the development of different forms of cancer. Here, Hsu et al[48] discovered that a worse prognosis for lung cancer patients is associated with elevated IL-10 levels. Furthermore, IL-10 levels were markedly elevated in the serum and lungs of mice with lung cancer caused by EGFRL858R and Kras4bG12D, suggesting that IL-10 may aid in the development of lung cancer. In EGFRL858R and Kras4bG12D mice, IL-10 deletion reduced the number of tumor-promoting Treg lymphocytes and infiltrating M2 macrophages while also preventing the growth of lung tumors[48].
Additionally, EGF boosts IL-10 production by improving IL-10 mRNA stability. IL-10 then triggers the signaling pathways JAK1/STAT3, Src, PI3K/Akt, and Erk. It is interesting to note that the recruitment of phosphorylated Src by IL-10 was essential for triggering EGFR via activating the JAK1/STAT3 pathway, indicating that Src and JAK1 positively regulate one another to increase STAT3 activity. Tumor development was low in doxycycline-induced EGFRL858R mice given gefitinib and anti-IL-10 antibodies. In summary, lung cancer develops as a result of the positive feedback between IL-10 and EGFR[48].
Treatment for NSCLC underwent a significant paradigm change thanks to immune checkpoint inhibitors (ICIs). However, an unpredictable pattern of immune-related adverse events (irAEs) is associated with the use of ICIs. Therefore, in order to avoid overtreating ICIs and lower the incidence of irAEs, more accurate biomarkers are required to predict the risk of irAEs. Medical professionals may use baseline and dynamic IL-10 plasma levels to track adverse events in patients receiving ICI medication because they are significantly and independently linked to an increased risk of developing irAEs[49].
Both IL-10 and IL-10R were shown to be elevated in the cells surrounding the lung tumor cells, and IL-10R was mostly expressed on the surface of Foxp-3+ T-regulatory lymphocytes infiltrating the patients’ tumors, where its expression was negatively linked with PD-L1. IL-10 reduced PD-L1 and tumor cell death in a human LUAD cell line, while IL-10R was shown to be increased under metabolic constraints prevalent during tumor development[50].
A multifunctional cytokine with immunosuppressive and anti-angiogenic qualities, IL-10 is crucial to the pathophysiology of cancer. Lan et al[51] showed that while the -1082G/A polymorphism did not affect lung cancer susceptibility, two polymorphisms (-592C/A and -819C/T) in the IL-10 gene’s promoter region were strongly linked to the risk of lung cancer.
The regulation of tumor development and metastasis may be significantly influenced by IL-10. IL-10 production by the tumor is a negative prognostic factor; others have demonstrated that IL-10 can be a powerful inhibitor of tumor development. Soria et al[52] examined the predictive significance of IL-10 in a well-defined sample of patients with stage I NSCLC treated in a single facility, since normal bronchial epithelial cells inherently generate IL-10. It is interesting to note that tumors with squamous cell histology have higher levels of IL-10 expression than tumors with other histological subtypes. The independent predictive significance of IL-10 expression for disease-specific survival[52].
Chemokines play a part in the development of lung cancer. Tumor cells and related tumor stromal cells release MCP-1 (also called CCL2). Neutralizing antibody-mediated CCL2 inhibition has been demonstrated to decrease carcinogenesis in a number of solid tumors; however, the significance of CCL2 in lung cancer is still debatable, with evidence of both protumorigenic and antitumorigenic effects. In a number of animal models of non-small-cell lung cancer, the impact and mechanisms of CCL2 inhibition. Syngeneic flank and orthotopic models of NSCLC were given anti-murine CCL2 monoclonal antibodies[53].
CCL2 blocking prevented lung metastases in a model of spontaneous lung metastases of NSCLC and considerably delayed the development of primary tumors in all models examined. Contrary to predictions, the number of tumor-associated macrophages recruited into the tumor following CCL2 inhibition did not show any discernible therapy impact. Nevertheless, upon CCL2 blockage, the polarization of tumor-associated macrophages changed to a more antitumor phenotype. Cytotoxic CD8+ T lymphocyte (CTL) activation was linked. In CB-17 severe combination immunodeficient animals or following CD8 T-cell depletion, the anticancer effects of CCL2 inhibition were eliminated[53].
A key modulator of monocyte recruitment during inflammatory processes is the chemokine MCP-1. Numerous tumors have been shown to contain tumor cells that express MCP-1 at pathologically high levels. Single-nucleotide polymorphisms (SNPs) of MCP-1 and its receptor, CCR2, have been implicated in the clinical relevance of NSCLC in a limited number of studies. The vulnerability to NSCLC was shown to be significantly correlated with the genetic polymorphisms MCP-1 and CCR2. Additionally, the severity of lung cancer was linked to these two SNPs[54].
Additionally, Cai et al[55] found from clinical serum specimens that patients with lung cancer who had bone metastases had higher levels of MCP-1 and IL-8 than those who had localized tumors. Next, it used monocytes generated from murine bone marrow to study the effects of MCP-1 on osteoclast development in vitro. Neutralizing antibodies against MCP-1 prevented the development of osteoclasts produced by A549 conditioned media. Lastly, MCP-1 short hairpin RNA was stably transfected into A549 cells. For four weeks, severe combination immunodeficient mice had MCP-1 knockdown A549 cells transplanted into their tibia. The MCP-1 knockdown dramatically reduced the proliferation of A549 cells. MCP-1 increases osteoclast activity caused by lung cancer and, therefore, bone resorptive lesions in vivo[55].
However, it is still unclear how tumor MCP-1 and CCR2 expression relate to NSCLC. MCP-1 expression was associated with tumor size, histology, smoking behavior, and sex. A higher OS rate was linked to MCP-1 presence in tumor cells. MCP-1 expression in cancer cells was found to be an independent predictor of OS using multivariate analysis. Clinical and pathological features were not significantly correlated with CCR2 expression in tumor cells. Additionally, Spearman correlation analysis did not show a significant positive association between MCP-1 and CCR2 expression. According to the findings, MCP-1 is overexpressed in NSCLC cells. Patients with NSCLC who express it in cancer cells have a higher chance of surviving[56].
Through its CCR2, MCP-1 plays significant roles in angiogenesis, wound healing, and inflammation. It is uncertain how inhaled nitric oxide (NO) and hyperoxia affect lung MCP-1 and CCR2 separately and together in connection to lung leukocyte dynamics. Ekekezie et al[57] postulated that inhaled NO with hyperoxia would boost MCP-1 synthesis and CCR2 expression more than either gas alone because oxidants upregulate the MCP-1 gene.
For one or five days before sacrifice, the young piglets were randomly allocated to breathe room air (RA), RA + 50 ppm NO, O2, or O2 + NO. In comparison to the RA group, the 5-day O2 and O2 + NO groups had substantially higher lung MCP-1 production and alveolar macrophage counts. In contrast, as compared to the RA group, lung CCR2 abundance was lower in the O2 group but not in the O2 + NO group. At 24 hours, no variation was seen in any of the variables examined[57].
Staining of alveolar septa, macrophages, vascular endothelium, and the luminal epithelial surface of airways revealed a comparable distribution of CCR2 in all groups. It was concluded that whereas hyperoxia raises MCP-1 in the lungs of young piglets, it simultaneously lowers CCR2 abundance, which might restrict MCP-1’s ability to participate in the recruitment of alveolar macrophages. Contrary to hyperoxia, inhaled NO has no discernible independent effect; nevertheless, when administered concurrently with hyperoxia, it lessens the negative impact of hyperoxia on CCR2 abundance[57].
Cancer start and progression are significantly influenced by MCP-1/CCL2. Tumor cells are thought to be the primary source of this chemokine since they generate MCP-1. By transplanting 4T1 breast cancer cells into the mammary pad of wild type (WT) or MCP-1−/− animals, Yoshimura et al[58] investigated whether MCP-1 generated by non-tumor cells influences the development and lung metastasis of these cells. Both mice’s primary tumors at the injection location developed identically, but MCP-1−/− mice had much longer animal life and significantly fewer lung metastases[58].
Tumors forming in WT mice showed high amounts of MCP-1 mRNA, but not in MCP-1−/− animals. Tumor-bearing WT mice had elevated serum MCP-1 levels, but not MCP-1−/− animals. While transplanting WT bone marrow cells into MCP-1−/− mice enhanced lung metastasis, transplanting MCP-1−/− bone marrow cells into WT mice had no effect on lung metastasis incidence. MCP-1−/− mice’s initial tumors consistently demonstrated lower angiogenesis and macrophage infiltration, as well as necrosis, earlier than those of WT mice. It is interesting to note that 4T1 cells that metastasised to the lung constitutively exhibited higher amounts of MCP-1, and intravenous injection of 4T1 cells that produced high levels of MCP-1 enhanced the number of tumor foci in the lungs of WT and MCP-1−/− mice[58].
NSE is a kind of glycolytic enolase isozyme and is regarded as a multifunctional protein. It is sometimes referred to as γ enolase or enolase-2. Apart from its well-known role in cytoplasmic glycolysis, NSE’s variable expression and altered cell location are linked to a number of illnesses, including cancer, autoimmune disorders, infection, and inflammation. The primary focus of Xu et al[59] study is NSE’s function and potential for diagnosis in certain lung conditions.
Additionally, individuals with NSCLC have a strong correlation between the targeted therapy success and the intracellular enzyme NSE. Another study aimed to investigate the relationship between NSE and the identification of gene mutations. The results of the work significantly improve the gene detection performance for lung cancer and clarify the functional role of NSE[60].
The biological roles of NSE, which is a particular biomarker for small-cell lung cancer, are poorly understood. Here, Lu et al[61] study clarifies the impact and mechanism of NSE on the stem cell-like properties of SCLC. Spheroid cells showed increased NSE expression. The gain-of-function and loss-of-function methods showed that NSE modulation favorably controlled SCLC cells’ stem cell-like traits, drug resistance, spherical clone creation, tumor development, and cell proliferation. According to mechanistic research, NSE may interact with NBL1 to downregulate its expression[61].
This would lessen NBL1’s competitive inhibitory effect on BMP2 and increase the interaction between BMP2 and BMPR1A, which could activate the BMP2/Smad/ID1 pathway and promote SCLC stem cell-like traits. Furthermore, the NSE-induced stem cell-like traits were reversed by either BMP2 knockdown or NBL1 overexpression. NSE expression was inversely connected with NBL1 expression and favorably correlated with ALDH1A1 expression in clinical specimens[61].
A monoclonal antibody (MCAB) against NSE has been used to evaluate the value of NSE immunoreactivity as a marker for SCLC. NSE immunoreactivity was seen in every SCLC sample analysed with this MCAB in radioimmunoassay and immunohistochemistry. However, some NSCLC cell lines and tumor biopsy specimens also showed significant reactivity. Reeve et al[62] showed that the expression of enolase in cells that were not actively proliferating was significantly different from that of cells that were growing exponentially. Additionally, compared to cells grown in oxygenated circumstances, cells grown in increasingly hypoxic conditions showed higher production of enolase[62].
NSE levels in serum and bronchoalveolar lavage fluid have been extensively studied in lung cancer; nevertheless, their diagnostic use has not yet been shown. S-NSE and B-NSE levels did not differ significantly across the groups. Smokers and nonsmokers, patients with SCLC and those without, and patients in stages I-II and III-IV of group 3 did not vary in S-NSE and B-NSE levels[63].
When compared to S-NSE in the diagnosis and/or staging of cancer, neither B-NSE nor B-NSE/urea demonstrated any relevance. The correlation between S-NSE and B-NSE was strong. The S-NSE has a 40% specificity and a 60% sensitivity. Karnak et al[63] concluded that whereas B-NSE elevation is a well-known indicator of SCLC, it can also be significantly raised in COPD and NSCLC. Since measuring S-NSE activity is simpler and less intrusive, it could be enough given the strong association between S-NSE and B-NSE. However, NSE can only be studied in a scientific context and has no bearing on the precise diagnosis of lung cancer[63].
TuM2-PK, CEA, and CYFRA21-1 serum levels were significantly higher in the NSCLC group than in the BLD and HC groups. In patients with NSCLC, serum levels of TuM2-PK, CEA, and CYFRA21-1 were linked to the tumor lymph node metastatic stage, lymph node metastasis and distant metastases[64].
Serum and tissue levels of IL-6 and TNF-α were significantly higher than those of controls; these levels were positively correlated with distant metastasis and lymph node metastasis; they were negatively correlated with E-cadherin levels and positively correlated with N-cadherin and vimentin levels. To sum up, IL-6 and TNF-α can cause the epithelial-mesenchymal transition, which in turn can encourage lung cancer spread[65]. Numerous molecules, including IL-8 and ET-1, can be stimulated by TNF-α. TNF-α expression was substantially linked to high levels of IL-8 mRNA and ET-1 mRNA positivity. Like IL-8 expression, TNF-α can cause ET-1 mRNA expression in NSCLC. Additionally, Boldrini et al[66] research might advance the understanding of the molecular connection between cytokines and endothelial activities in NSCLC.
The primary effectors of innate lymphoid cells of the type 2 innate immune response are IL-4 and IL-13, which can transmit particular signals amongst many cells in the tumor immunological microenvironment. Through their common receptor chain, the transmembrane heterodimer IL-4 receptor alpha/IL-13 receptor alpha-1 (type II IL-4 receptor), IL-4 and IL-13 mediate signal transmission and control cellular processes in a range of solid tumors. Numerous malignant tumors may be induced to develop, and IL-4, IL-13, and their receptors are crucial for the growth, progression, and tumor immunity of these cancers[67].
As conclusion, CEA, SCC, CYFRA 21-1, TNF-α, GM-CSF, IFN-γ, ILs IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, MCP-1 and NSE contribute to lung cancer pathogenesis through multiple mechanistic pathways, including promoting tumor cell proliferation, survival, and metastasis; modulating apoptosis and immune evasion; enhancing inflammatory and angiogenic responses; supporting neuroendocrine differentiation; and facilitating tumor-microenvironment interactions that drive tumor progression and aggressiveness as explained in Tables 1 and 2 and Figures 1, 2 and 3.
Tumor markers and cytokines serve as non-invasive biomarkers that provide insights into lung cancer biology. Clinically, they are valuable for early diagnosis, prognosis, therapy monitoring, and guiding personalized treatment, ultimately helping to improve patient management and outcomes. Certain cytokines have been linked to lung cancer mortality and prognosis, according to recent clinical research. It was unclear, therefore, how cytokines and clinical outcomes related to individuals with severe lung cancer. Research indicates that IL-1β and a few of its downstream effectors, such as IL-6, IL-8, C-reactive protein, and cyclooxygenase-2, may be used as prognostic indicators in a variety of cancers, including lung cancer[35]. In addition to assisting in the diagnosis of lung cancer, CEA is also used to track recurrence, assess the prognosis, and assess the effectiveness of lung cancer treatments[11].
In patients with advanced NSCLC who had a high CEA at baseline and had only had one chemotherapy cycle, a drop in CEA level is a sensitive and specific measure of an objective response as well as a sensitive signal for progression to chemotherapy. A prolonged progression-free survival is linked to a 14% decrease in CEA levels[68].
Regardless of therapy or study design, the serum level of CEA offers prognostic and predictive information about the probability of mortality and recurrence in NSCLC. It is intriguing to note that the tumor marker index may be a useful prognostic indicator for OS in NSCLC[69]. CEA may offer an alternative to scans in long-term responders undergoing targeted treatment, but its low sensitivity to predict disease progression limits its usefulness for monitoring[12].
A possible predictive and diagnostic indicator for advanced lung cancer is the serum CK19 fragment[6]. Compared to other indicators, such as CEA and SCC-related antigen, cytokeratin 19 fragment was shown to be more sensitive[17]. SCC had the highest sensitivity (76.1%), whereas SCLC had the lowest sensitivity (44.4%). Patients with mediastinal lymph node metastasis (N2 or N3) showed higher serum CYFRA 21-1 levels than patients without mediastinal node metastasis. The discriminatory value of CYFRA 21-1 was compared to that of other tumor markers, such as NSE, CEA, and SCC antigen. Of the markers examined for lung cancer detection, CYFRA 21-1 seemed to have the highest discriminating potential. Serum levels of CYFRA 21-1 and the degree of clinical response were shown to be highly correlated in serial assessments of 14 patients undergoing chemotherapy or radiation[70].
Given that CYFRA 21-1 is frequently employed as a tumor marker for lung cancer, it is important to take note of the information, particularly in patients who have received radiation[19]. CK19-2G2 might be a potential marker for lung cancer diagnosis and therapy response monitoring. Furthermore, in individuals with lung cancer, CK19-2G2 could be a sign of micrometastases[21].
Serum levels of TuM2-PK, CEA, and CYFRA21-1 have high clinical values in the diagnosis of NSCLC and may accurately assess a patient’s prognosis[64]. When treating pulmonary alveolar proteinosis, aerosolized GM-CSF is a safe and efficient substitute for whole-lung lavage or subcutaneous GM-CSF[71]. Differential reactions to biological and cytotoxic treatments have changed how it approaches conventional treatments. The identification of SOX2 amplification, NFE2 L2 and KEAP1 mutations, alterations in the PI3K pathway, FGFR1 amplification, and DDR2 mutations has also revealed evidence of distinct biology. A new era of specific therapy medicines for patients with this illness has been started by these findings[16].
According to recent research, targeted therapy with EGFR inhibition causes a fast elevation of TNF in NSCLC, which triggers NF-κB activation. Both primary and secondary resistance to EGFR inhibition in NSCLC are mediated by TNF overexpression and subsequent NF-κB activation, and in experimental models, therapeutic resistance may be overcome by combining EGFR and TNF inhibition. TNF may regulate resistance to ICIs and influence the harmful side effects of immunotherapy. TNF-inhibiting medications are often used to treat a variety of rheumatologic and inflammatory conditions, and they may be very helpful when combined with targeted therapy for NSCLC and other malignancies[24].
Based on the TNF-α-mediated genes that were dysregulated in lung tumors, Wang et al[25] developed a prognostic gene signature that accurately predicted recurrence-free survival in lung cancer in two validation cohorts based on the TNF-α-mediated genes that were dysregulated in lung cancers. Multivariate analysis indicated that this gene signature was independent of the conventional clinical factors and improved the identification of lung cancer patients at higher risk for recurrence, and resampling tests indicated that the prognostic power of the gene signature was not by chance[25].
With an emphasis on lung cancer, TNFR1/2 functions and biomarker potential to predict cancer development and response to immunotherapy are addressed. Further show that, whereas the TNFR1/TNFR2 balance is elevated in lung cancer patients, the expression levels of TNF and TACE are markedly reduced by mining existing sequencing data[23].
Through the production of reactive oxygen species, such as superoxide and hydrogen peroxide, certain immunotherapies (TNF, IL-1, IL-2, and IFN-γ), chemotherapeutic agents [mitomycin, platinum, doxorubicin (adriamycin), and bleomycin], and radiation therapy have been shown to cause cytotoxicity. However, it has been demonstrated that TNF increases resistance to reactive oxygen species stress, such as radiation treatment and oxygen toxicity, both in vitro and in vivo. This may be due to the production of higher cellular buffering capacity. It is unclear if TNF, which induces free radical scavenging enzymes such as manganese superoxide dismutase, modifies a lung cancer cell’s susceptibility to reactive oxygen species treatment. Pogrebniak et al[72] examined the A549 LUAD cells that were treated with hypoxanthine plus xanthine oxidase, a system that produces superoxide, at different intervals after being exposed to 0 μg/mL, 0.1 μg/mL, 1.0 μg/mL, or 10 μg/mL doses of TNF for a whole day.
The number of cells that survived the stress for five days was counted, and the activation of the manganese superoxide dismutase gene in cells exposed to TNF was assessed. TNF pretreatment markedly improved cell survival, although hypoxanthine-xanthine oxidase stress alone resulted in a time-dependent decline in survival. Additionally, the amount of manganese superoxide dismutase transcripts increased fivefold in the cells exposed to TNF. These results imply that lung cancer cells may be resistant to later reactive oxygen species-based treatments due to TNF and that this resistance may result from elevated manganese superoxide dismutase expression. TNF administration in conjunction with other treatments may lead to clinical treatment failures[72].
IFNs are used to treat lung tumors. Additionally, IFNs may have proapoptotic, immunoregulatory, antiangiogenic, and antiproliferative properties. IFN-γ is an anticancer drug that combats many types of cancer. Both types of IFN-γ, such as IFN-γ bulk and IFN-γ nanoliposome may be useful in the treatment of lung cancer, and it has been demonstrated that IFN-γ liposomes may lessen DNA damage more than the bulk form[73]. Chemokines in the CXCR3/Ligand axis that are induced by IFN-γ are important in the development of cancer and are implicated in cell-mediated immunity. The serum IFN-γ-inducible chemokines may be useful as clinical indicators of metastasis and prognosis in NSCLC[74].
These findings suggested that RNase L is a therapeutic target in lung cancer cells, and IFN-γ immunotherapy might be used as an adjuvant to increase the effectiveness[32].
There are few worldwide treatment options for lung cancer, which is recognised as one of the most deadly malignancies in the world. Problems include delayed diagnosis, limited treatment options, recurrence, and the development of medication resistance, which hinder the effectiveness of treatment. Due to this dilemma, lung cancer therapy has reached a saturation point, which has caused the TME to become a crucial field of cancer research. IL-1, which comes from immune cells, tissue stromal cells, and tumor cells, is widely distributed inside the TME. The pro-inflammatory mediators and chemokines that IL-1 induces create an inflammatory milieu that affects the formation, incidence, and interaction of malignancies with the host immune system. Notably, IL-1 expression in the TME demonstrates traits such as tissue selectivity, staging, and functional pluripotency[75].
The process of inflammation allows organs to heal and shields them from a variety of potentially dangerous stimuli. On the other hand, dysregulated inflammation causes tissue damage and illness, including cancer. Cytokine production, leukocyte infiltration, angiogenesis, and tissue remodeling which are all essential mechanisms in regulating the TME are characteristics of cancer-related inflammation. Immunotherapy is based on targeting the immunological component of the TME, which is known to play a significant role in tumor growth, to improve the anti-tumor response. Aldesleukin, a human recombinant IL-2 protein, is the only United States Food and Drug Administration-approved treatment that directly uses cytokine signaling, despite the crucial role cytokines play in the TME and tumor growth. In addition to evaluating the effectiveness of anti-IL-1β medication in atherosclerotic disease, the recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study also found that IL-1β blocking with canakinumab dramatically reduced the risk of lung cancer. Anti-IL-1β therapy alone or in conjunction with chemotherapy and/or immune checkpoint inhibition is now being assessed in a number of clinical trials, opening a potential new route for the treatment of lung cancer[76].
The current standard of care, which includes chemotherapy and ICIs like anti-PD-1/PD-L1 antibodies, is still ineffective for many patients with NSCLC. Although IL-1β is known to stimulate the growth of lung cancer in both humans and mice, Perrichet et al[77] aimed that in mouse lung cancer models, IL-1β injection or overexpression overcomes resistance to traditional chemo-immunotherapy (cisplatin/pemetrexed/anti-PD-1). IL-1β’s anticancer effects depend on CXCL10 produced from cancer cells, which facilitates CD8 T cell recruitment to the tumor site. TXNIP causes the release of mitochondrial DNA in the cytoplasm of lung cancer cells. This activates the AIM2 inflammasome, which in turn causes the production of CXCL10 and IL-1β, reversing chemo-immunotherapy resistance. The transcriptome study of patient tumors, which shows that high expression of IL-1β, IL-1R1, AIM2, and/or TXNIP is linked to a greater response to immunotherapy in NSCLC patients, supports the clinical significance of these findings. Furthermore, pharmacological screening reveals that MDM2 and MEK inhibitors can reverse chemo-immunotherapy resistance by inducing TXNIP expression. IL-1β has a beneficial effect in the treatment of lung cancer, and increasing IL-1β production at the tumor site might help overcome chemo-immunotherapy resistance[77].
K-ras-mutant LUAD (KM-LUAD) is closely connected to inflammation that promotes tumor growth and has a poor prognosis. In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study, a human MCAB called canakinumab, which targets the proinflammatory cytokine IL-1β, dramatically reduced the incidence of lung cancer. It's interesting to note that animals with K-rasG12D-mutant tumors (CC-LR mice) have elevated levels of IL-1β in their lungs. Here, Yuan et al[78] investigated the preventative and therapeutic effects of blocking IL-1β in cohorts of 6- or 14-week-old CC-LR mice using an anti-IL-1β mAb. The lung microenvironment was reprogrammed toward an antitumor phenotype with increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 expression), while neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells were suppressed. IL-1β blockade significantly decreased the burden of lung tumors. Yuan et al[78] discovered strong connections between IL-1B expression and immunosuppressive PMN infiltration and the expression of their chemoattractant, CXCL1, and PDCD1 in patients with KM-LUAD when querying the Cancer Genome Atlas data set. IL-1β blocking might be a preventative measure for high-risk patients as well as an alternate therapeutic strategy when used in conjunction with existing KM-LUAD therapies[78].
In severe small-cell lung cancer (stage IIIB or IV), hemotherapy may result in overall (complete plus partial) response rates of over 50% and complete response rates of up to 25%; nevertheless, survival is often restricted to 8-12 months. IL-2 has shown efficacy against this illness in vitro and has caused renal cell carcinoma and melanoma to regress. The response rate was 21% overall. Three patients experienced full responses for 8 months, 9 months, and over 11 months; the other patient experienced acute myelomonocytic leukaemia while in complete remission about 8 months after beginning IL-2 treatment. Out of the twenty-four patients, only five managed to finish the eight weeks of IL-2 treatment. Eleven patients had their therapy stopped due to potentially fatal adverse effects, six due to the advancement of their illness, and two withdrew from the research, most likely due to IL-2 toxicity. These findings imply that IL-2 is not cross-resistant with PACE treatment and show some activity in extensive small-cell lung cancer[79].
Also, down-regulation of IL-2 is linked to immune escape and predicts a poor prognosis in LUAD, suggesting that IL-2 might be a new prognostic biomarker of LUAD[38].
Th1-type cytokine IL-2 has been demonstrated to be crucial for antitumor immune responses. In 60 patients with advanced non-small-cell lung cancer, the predictive importance of blood IL-2 levels was examined. Serum levels of IL-2 were found to be greater in all 60 patients compared to controls. While IL-2 levels remained substantially higher than those of controls, they were significantly lower in stage IV patients compared to stage III patients. Interestingly, when patients were separated into responders and non-responders based on how well they responded to treatment, the former had far greater pre-chemotherapy levels than the latter. Furthermore, at the conclusion of treatment, IL-2 blood levels were significantly higher in responders and significantly lower in non-responders. The mean pathogenic levels of IL-2 were found to have an impact on both OS and time to treatment failure using both univariate and multivariate analyses. Additionally, the predictive importance of the blood level of IL-2. In conclusion, it has been demonstrated that determining pre-treatment IL-2 serum levels has independent prognostic usefulness in patients with advanced NSCLC; hence, its potential application for outcome prediction is suggested[80].
IL-4 receptors are expressed by human lung tumor cell lines, according to earlier research, and IL-4 can mediate mild to moderate antiproliferative action both in vitro and in vivo in animal models of human lung cancers. IL-4 was evaluated in clinical trials based on these findings; it had minimal anticancer efficacy in patients with lung cancer. Kawakami et al[81] looked at the expression of IL-4Rs in lung tumor samples and normal lung tissues, and investigated whether a drug targeting IL-4R would be more effective against tumors both in vitro and in vivo than IL-4.
Protein synthesis inhibition and clonogenic tests were used to investigate the cytotoxic effect of IL-4 cytotoxin [IL-4(38-37)-PE38KDEL], which is made up of a circular permuted IL-4 and a mutant version of Pseudomonas exotoxin (PE38KDEL), in seven lung carcinoma cell lines. Both in vitro and in immunodeficient animal models of human lung cancers were used to assess the antitumor efficacy of IL-4 cytotoxin. It found that lung tumor samples express more IL-4Rs in situ than normal lung tissues, and that IL-4 cytotoxin is very and selectively lethal to lung tumor cell lines in vitro. Intratumoral and intraperitoneal administration of IL-4 cytotoxin to immunodeficient mice with subcutaneous injection established human lung H358 NSCLC tumors mediated considerable antitumor activity in a dose-dependent manner, with the higher dose producing durable complete responses. However, IL-4 cytotoxin treatment was ineffective against H460 NSCLC tumors that expressed low amounts of IL-4R[81].
Kawakami et al[81] suggest studying the safety of this medication in patients with lung cancer since IL-4 cytotoxin mediates its anticancer action through IL-4R, and a variety of lung cancers exhibited high levels of IL-4R. A common pleiotropic Th2 cytokine implicated in immunology during carcinogenesis is IL-4. When compared to the CC wild-type genotype, the TT genotype of IL-4 C-589T may have a protective impact on lung cancer risk in Taiwan and may be a marker for early identification and prediction[82].
The immune system’s activation against cancerous cells is largely dependent on cytokines. Because of its strong immunoregulatory properties, IL-4, one of these cytokines, has started clinical phase I studies. Topp et al[83] reported that recombinant human (rh) IL-4 has significant direct antiproliferative effects on one CCL 185 in vitro, as determined by counting cell numbers and marginal activity in a second cell line (HTB 56) in the human tumor cloning assay (HTCA), tritiated thymidine uptake, and a HTCA. The expression of human IL-4 receptors at both the mRNA and protein levels is associated with the tumor cells’ biological response to the cytokine. After being exposed to rhIL-4, the responsive cell line CCL 185 releases IL-6. However, the growth modulatory effectiveness of rhIL-4 in this cell line was unaffected by neutralizing antibodies against IL-6. Moreover, during incubation with rhIL-4, CCL 185 did not exhibit any discernible production of IL-1, TNF-α, or IFN-γ[83].
Therefore, rhIL-4-induced autocrine synthesis of these cytokines does not modulate the response to rhIL-4. Some of the cell lines were xenotransplanted into BALB/c nu/nu (a specific strain of immunodeficient mouse) mice in the subsequent set of tests. The mice were then given two subcutaneous doses of 0.5 mg/m2 rhIL-4 or control vehicle every day for a duration of 12 days. Two of the NSCLC cell lines that were sensitive in vitro showed a substantial reduction in tumor development when treated with rhIL-4 (CCL 185, HTB 56). According to IL-4’s species specificity, the histology of the tumors in both groups revealed no discernible infiltration of mouse hematopoietic and lymphocytic cells. On the other hand, the SCLC cell lines (HTB 119, HTB 120) were nonresponsive in vitro and showed no tumor growth suppression. Together with its regulatory effects on different effector cell populations, it was concluded that rhIL-4 has direct antiproliferative effects on the growth of some human NSCLC cell lines in vitro and in vivo. This makes this cytokine an intriguing candidate for additional research in experimental cancer treatment[83].
Together, results demonstrate the role of the IFN-I/IL-4 axis in antitumor immunity, which may be used to target and classify solid tumors that do not respond to first-line treatments[84]. Another study's findings highlight an as-yet-undiscovered function of IL-6/STAT3 signaling in preserving lung homeostasis and preventing the development of lung cancer[40].
The incidence of cancer is sharply increasing as a result of fewer treatments being available and postponed clinical research. This may be a result of chemotherapy medications and immunological modulations that increase cancer resistance. Among them, host-derived paradoxical effectors that modify immune responses in cancerous lung cells include IL-6 and IL-17. Cellular disruptions are caused by their excessive release in the cytokine milieu, which stabilizes immunosuppressive phenotypes. These molecules are important during tumor formation because they can control oncogenesis by starting a variety of signaling events that affect tumor growth and the capacity of benign cancer cells to spread. Additionally, by constitutive expression of immunoregulatory molecules, their transactivation promotes cancer cell survival and supports antiapoptotic processes. The main forces underlying cytokine development may be co-evolution and gene duplication occurrences, which have led to generic alterations and, thus, the additive impact. Given that both cytokines share cysteine-knot-like features crucial for preserving structural integrity, the evolutionary model and statistical analysis offer more compelling evidence for the cytokines’ ancestral links and site-specific conservation. Finding residues that have a catalytic role in immune function may be possible by sorting through the results. The aetiology of lung cancer may be prevented by using peptides or subunit vaccine formulations that target those conserved residues[85].
In addition to being a promising biomarker for predicting a poor prognosis and potential therapeutic targets in NSCLC, IL-6 is a cytokine that plays a significant role in response to damage or infection. Another study highlights the diagnostic and prognostic usefulness of IL-6 levels and examines the molecular process, function, and genotype of IL-6. In the future, anti-IL-6 medication might be used to treat irAEs since it improves the anticancer activity of immunocheckpoint inhibitors without affecting their impact. As a result, IL-6 might be a therapeutic target for NSCLC[86].
In individuals with severe lung cancer, elevated IL-6 levels are a crucial predictor of progressive disease. To improve the prognosis of patients with severe lung cancer, it may be crucial to monitor the IL-6 level[43]. Wang et al[87] observed that cytokines control the immune response. Therefore, improving results and creating novel therapeutic approaches depend on understanding the determinative cytokines of response to immune-checkpoint inhibitors[87].
Next, Wang et al[87] found that NSCLC patients with progressing disease had significantly higher baseline levels of IL-6 in their plasma samples and tumor tissues. Baseline IL-6 levels were found to be an independent prognostic predictor. Furthermore, in the tumor tissues, there was a negative association between IL-6 and CD8+ T cells and a positive correlation between IL-6 and PD-L1 expression. According to the in vitro research, IL-6 increased PD-L1 expression in tumor cells through the IL-6-JAK/Stat3 signaling pathways. According to the in vivo research, IL-6 and PD-L1 antibody blockade combination therapy reduced the growth of tumors in NSCLC mice. By increasing the phenotypic characteristics and infiltration of CD8+ T cells, targeting IL-6 may increase the effectiveness of ICIs. Baseline IL-6 plasma levels might become a potent predictor of immunotherapy. The advancement of IL-6 as a therapeutic target for cancer treatment is made possible by these findings, which show that targeted reduction of IL-6 may improve the effectiveness of anti-PD-L1 in NSCLC[87].
The association between elevated IL-8 and CXCR1 expression and worse OS in patients with resected lung cancer was validated by analysis of TCGA RNA-seq data. To the best of the knowledge, Belluomini et al[88] study is the first meta-analysis showing that high IL-8 levels have a detrimental predictive effect in lung cancer, especially in patients receiving chemotherapy and/or immunotherapy.
In response to various stimuli such as LPS, TNF-α, IL-1, IL-7, and hypoxia, alveolar macrophages, endothelial cells, monocytes, fibroblasts, T lymphocytes, and epithelial cells release IL-8, an 8 kD chemokine and angiogenic factor. Numerous growth factors and cytokines that may have both autocrine and paracrine effects are produced by pulmonary tumors. These results imply that IL-8 may prevent lung tumor growth through both autocrine and paracrine mechanisms, in addition to its chemotactic and angiogenic properties[89].
IL-8 is a cytokine that affects both the TME and immune escape mechanisms and is essential to the development and spread of NSCLC. Given its importance, precise measurement of IL-8 levels at the protein and RNA levels may offer important information about its prognostic relevance and guide treatment targeting approaches. In order to perform a thorough assessment of IL-8 expression in NSCLC, Ramos et al[90] study integrates both protein presence and gene expression analysis within the geographical context of the TME using imaging mass cytometry (IMC). According to preliminary evidence, there is a significant degree of variability in the distribution of IL-8 at both the protein and RNA levels, with specific patterns that are related to immune infiltration and tumor aggressiveness developing. The integrated IMC approach revealed that high IL-8 expression is associated with poor prognosis and decreased responsiveness to conventional treatments, highlighting its potential as a biomarker for the treatment of NSCLC. Additionally, the microenvironmental niches where IL-8-mediated interactions may promote tumor development and immune evasion are highlighted by the geographical analysis provided by IMC. Ramos et al[90] work offers a thorough understanding of the role of IL-8 in lung cancer pathology by using IMC for the dual analysis of IL-8 protein and RNA in NSCLC.
Understanding IL-8’s biological effects and creating targeted treatments are made possible by the capacity to see and measure its expression in the geographical context of the TME. With possible ramifications for patient categorization and individualized therapy planning, these results support the inclusion of IL-8 in the NSCLC biomarker panel. In order to improve NSCLC outcomes, future studies will concentrate on extending these findings to a broader cohort and investigating the therapeutic manipulation of IL-8[90].
Tumors are very complicated structures. While a superordinate structure is still mostly unknown, the plurality of their structural and functional components—heterogeneity, variety, directionality, dependency, and integration of signaling pathways- seems to follow distinct local norms. The foundation for identifying causes and creating successful cancer treatments is an understanding of its complexity. A strong pro-inflammatory chemokine, IL-8, is markedly increased in a variety of tumor types. A growing number of research studies have been published in recent years that associate this chemokine with tumor-promoting characteristics and a bad prognosis, in contrast to its previously suggested anti-tumor effects[91]. IL-8 is considered a potential biomarker for poor prognosis in lung cancer patients. Therapeutic strategies, such as inhibiting IL-8 or its receptors (CXCR1/CXCR2), are being investigated to mitigate tumor progression, reduce angiogenesis, and reverse resistance to therapy.
IL-10 counteracts the effects of IFN-γ on the PD-1/PDL-1 pathway, potentially making the tumor resistant to anti-PD1/PD-L1 immunotherapy[59]. The type 2 cytokine IL-10 inhibits the regional immunity's antitumor efficacy against a variety of neoplasms. Although IL-10 is produced by some lung tumors, the clinical relevance of IL-10 expression is unclear. Hatanaka et al[92] showed that IL-10 expression is a predictive factor for NSCLC and that cytoplasmic IL-10 is linked with clinical outcome.
One of the main cytokines that plays a crucial role in the immune system’s pro-tumor and immunosuppressive actions is IL-10. Tumor-associated macrophages, T regulatory cells (Tregs), Th2 cells, and bronchial epithelial cells—the first biological source of NSCLC are the primary producers of IL-10. Furthermore, Th1 cells, antigen-presenting cells, and classical-activated macrophages, all crucial for tumor defense, can be inhibited by IL-10. Loss of IL-10 improves the microenvironment’s anti-tumor immune response, making it a potential target for immunotherapy[93].
Both immunological and malignant cells secrete IL-10, which accelerates the growth of lung cancers and adversely affects patient prognosis. PI3K/AKT inhibitors may sensitize cancer cells to chemotherapy, encouraging tumor regression and improving clinical prognosis, as IL-10 promotes carcinogenic effects through the PI3K/AKT signaling pathway[94]. Oncogenes and the inflammatory microenvironment interact in a complicated way to cause lung cancer. Specifically, less is known about how the cytokines, including TNF-α and IL-1β, affect important regulators such as WT1 and IL-10. Another study is to look at how these cytokines affect WT1 and IL-10 regulation as lung cancer advances. These results imply that inflammatory cytokines influence WT1 and IL-10 in a stage-dependent way in lung cancer. Increased IL-10 expression is linked to WT1 overexpression, especially in advanced stages, suggesting possible therapeutic targets for influencing the immune response in lung cancer[95].
IL-10 suppresses the activity of Th1 cells and antigen-presenting cells, inhibiting the immune system’s ability to attack tumor cells. High IL-10 expression within tumor cells is a significant marker for poorer prognosis and reduced survival in NSCLC patients. Due to its role in establishing a tumor-tolerant microenvironment, targeting the IL-10 pathway is considered a potential therapeutic strategy to enhance the efficacy of cancer treatments. However, accumulating evidence indicates that IL-10 exerts complex, context-dependent effects.
Two major issues with the treatment of human small-cell lung cancer are distant metastases and multidrug resistance. Nokihara et al[96] examined whether the anti-P-gp MCAB (MAb) MRK16 inhibited the production of metastases or if transduction of the MCP-1 gene into multidrug-resistant (MDR) human lung cancer cells influenced this process. The human MCP-1 gene was transduced into MDR human SCLC (H69/VP) cells using the expression vector BCMGSNeo. Drug sensitivity, surface antigen expression, and H69/VP cell proliferation in vitro were unaffected by MCP-1 gene transduction. H69/VP cells transduced with the MCP-1 gene were injected intravenously using the metastatic paradigm of natural killer cell-depleted SCID mice. These cells produced metastatic colonies in the liver, kidneys, and lymph nodes that resembled those produced by parent or mock-transduced cells. On the other hand, systemic administration of MRK16 to the mice decreased the metastases of H69/VP cells in the liver, kidneys, and lymph nodes, and it was much more successful than mock-transduced cells in preventing the metastases of MCP-1-generating H69/VP. The longevity of tumor-bearing mice treated with MRK16 was considerably extended by MCP-1 gene transduction. Local MCP-1 synthesis at the tumor site boosts anti-P-gp antibody-dependent cell-mediated cytotoxicity, and the MCP-1 gene-induced change of MDR human SCLC cells therefore improves the anti-P-gp antibody therapy's antimetastatic efficacy. Therefore, a crucial component of the anti-P-gp antibody treatment is the buildup of effector cells in the tumor location[96].
Blocking MCP-1 has been shown to reduce primary tumor growth and decrease spontaneous metastasis in preclinical lung cancer models. Studies indicate that modifying or blocking MCP-1, or its receptor CCR2, could increase the efficacy of existing cancer therapies (e.g., anti-P-glycoprotein antibodies).
In individuals with SCLC, low NBL1 expression and high NSE and ALDH1A1 levels were linked to a poor prognosis. It was shown that NSE stimulated the BMP2/Smad/ID1 pathway and NBL1 to induce stem cell-like traits of SCLC[61].
One of the most prevalent indicators of SCLC and a frequent tool for lung cancer screening is NSE. However, a variety of circumstances alter its specificity. NSEcorrected is more appropriate for large population screening, might enhance the screening impact of SCLC, lower the false positive rate, and maximize the distribution of lung cancer resources[97]. NSE immunoreactivity in and of itself is a poor indicator of the SCLC phenotype[62].
For individuals with small-cell lung cancer, serum NSE levels have been linked to a poor prognosis. In multivariate analysis, time to progression and survival were independently predicted by pretreatment NSE levels and treatment-induced minimal NSE values. The development of particular correlations between NSE and time to advancement and survival was made possible by hazard rate modeling. In these SCLC patients, pretreatment NSE levels were negatively linked with survival and time to progression. The 28% of the difference in survival was explained by pretreatment NSE. Time to progression and survival were independently predicted by both pretreatment NSE and treatment-induced minimal NSE[98].
One of the most prevalent indicators of small-cell lung cancer and a popular tool for lung cancer screening is NSE. However, a variety of circumstances influence its specificity. NSEcorrected performed superiorly in screening, according to ROC, calibration, and decision analysis curves. For easier use, the NSEcorrected computation was transformed into an online R-based application. NSEcorrected is more appropriate for large population screening, might enhance the screening impact of SCLC, lower the false positive rate, and optimise the distribution of lung cancer resources[97].
Multiparameter binary logistic regression diagnostic model that included CEA, CY211, IL-8 and TNF-α for the auxiliary detection of lung cancer. Compared with conventional CEA, it significantly improved diagnostic accuracy[8].
In lung cancer, cytokines are crucial for immunity. Cytokines are essential to the immune system and can be created therapeutically in the laboratory. The immune system is assisted by cytokine treatment in preventing or eliminating cancer cells, particularly lung cancer cells. To elicit a positive response in cancer patients, high dosages of cytokines are necessary, doing so causes several issues, such as their toxicity and short lifetime. To better target cytokines and change their adverse effects, new technologies are being developed[4].
Researchers should do a thorough investigation of lung disease types, patient age, and concomitant conditions if CEA levels increase[11]. A viable therapeutic strategy for treating NSCLC may involve targeting CEA or the PKA-PGC-1 signaling pathway[13]. A case study shows that measuring CEA levels can improve diagnostic sensitivity in cases with cytologically negative pleural effusions suspected of being malignant. It provides important information when determining whether to follow up on pulmonary nodules or perform ongoing diagnostics like video-assisted thoracoscopic surgery wedge resection[14]. A more accurate index for lung cancer prognosis and recurrence than is achievable with the use of single biomarkers may be created by analyzing many indicators simultaneously in future research[69].
Clinicians may be able to determine which SCC patients should undergo adjuvant chemotherapy (CTx) by using baseline CYFRA 21-1 and CEA values. These biomarkers need to be further examined[99]. Further characterisation of the fragment and its release during epithelial malignancies, such as NSCLC, is essential to producing useful biomarker tests, given the disparate CYFRA 21-1 concentration estimations among assays[100]. However, considering the contradictory in vitro evidence about growth stimulation, more research is required to resolve this matter. To determine if the hematopoietic protective effect affects response and survival, more research is also required[101]. By controlling inflammatory cytokines, GM-CSF has been demonstrated to be a significant modulator of radiation-induced lung damage, offering a novel approach to its prevention and therapy[102].
Lung SCCs, also known as squamous cell lung malignancies, are linked to a high death rate and a dearth of disease-specific treatments. Even though LUSCs frequently exhibit molecular abnormalities, efforts to create targeted treatments targeting receptor tyrosine kinases, signaling transduction, and cell cycle checkpoints in LUSCs have encountered considerable difficulties. The current therapeutic landscape is centred on using epigenetic therapeutics to control the expression of undruggable oncogenes and lineage-dependent survival pathways. Taking advantage of LUSC-specific metabolic vulnerabilities is a crucial treatment strategy. In the appropriate therapeutic setting, these new treatments could work in concert with ICIs. For instance, the discovery that changes in KEAP1-NFE2L2 in LUSCs influenced anticancer immune responses opened up novel possibilities for immunological, metabolic, and targeted combinations. Lau et al[103] offer a viewpoint on how the current treatment environment and prospects for future medication development for LUSCs are influenced by lessons learnt from the past.
TNF has been used to treat some forms of cancer and can cause cancer cells to die[24]. Lung cancer should be treated with anti-inflammatory medications[65]. Like IL-8 expression, TNF-α can cause ET-1 mRNA expression in NSCLC. Additionally, research may advance our understanding of the molecular connection between cytokines and endothelial activities in NSCLC[66]. Biomarker potential of TNF-α alone will probably not yield definitive results, but TACE might play a crucial role in addition to the delicate balance of sTNF-α/tmTNF-α and TNFR1/TNFR2. This highlights the significance of further research into the potential of rationalized treatments that combine immunotherapy and TNFα pathway modulators for patients with lung cancer[23].
The structure, biological roles, and importance of TNFRSF in cancer are the main subjects of this review. In an effort to provide fresh insights into cancer diagnosis and therapy, it investigates immunotherapeutic applications, targeted pharmacological therapies, and biomarker possibilities. Nevertheless, there are still obstacles in the way of turning these discoveries into successful treatments, and more study is required to overcome these obstacles and enhance the prognosis for cancer.
Cao et al[30] demonstrate how apCAFs undermine the effectiveness of neoadjuvant chemoimmunotherapy and suggest using anti-PD-L2/RGMB regimens to target apCAFs and work in concert with anti-PD-1 treatments. Kratzmeier et al[31] findings reveal what is believed to be a novel and until now unidentified immunoregulatory route unique to lung cancer that might be used to customise immune-based treatment for this particular illness. Also, Tan et al’s findings[36] demonstrate that IL-1β connects inflammation to glycolysis in LUAD, and that IL-1β and the glycolysis pathway may be targets for lung cancer treatment. To ascertain if IL-2 can be used to treat small-cell lung cancer, more research is required to discover the best time, dosage, and regimen for the drug[79].
Additionally, these investigations greatly advance our knowledge of lung cancer and offer a biological foundation for developing IL-6/STAT3-targeted treatments for the deadliest kind of cancer in humans[40]. A markedly poorer prognosis for early-stage NSCLC was linked to the tumor's lack of IL-10 expression. Further investigation is required to determine the processes behind this physiologically and clinically significant result[52]. The findings from NSCLC models demonstrate that CCL2 inhibition can prevent primary and metastatic disease tumor development. Tumor macrophage phenotypic changes and CTL activation are two of the mechanisms of CCL2 inhibition. The findings encourage more research on CCL2 blockage in thoracic cancers[53].
Therefore, lung metastasis of 4T1 cells is facilitated by stromal cell-derived MCP-1 in initial tumors; however, once tumor cells enter the bloodstream, tumor cell-derived MCP-1 might also play a role. Novel approaches to cancer treatment may result from a better knowledge of the origin and function of MCP-1[58]. One of the most prevalent indicators of SCLC and a frequent tool for lung cancer screening is NSE. However, a variety of circumstances alter its specificity. The 58 patients with SCLC had serial measures of NSE evaluated retrospectively. Serial assessments of serum NSE appear to be at least a helpful addition to traditional exploratory methods to guide the treatment of SCLC, as they can predict the occurrence of a large response, stable illness, and progressing disease outside the brain with very good accuracy[104]. Future research examining the possibility of NSE as a silicosis marker may build upon the case report[105].
Lung cancer, inflammation, the inflammatory milieu, and chronic infection are all strongly correlated, according to clinical and epidemiological research. Finding new treatment targets for lung cancer can be facilitated by gradually comprehending the tumor inflammatory microenvironment, which helps to better understand the association between inflammation and lung cancer[106].
The CEA, SCC, CYFRA 21-1, TNF-α, GM-CSF, IFN-γ, ILs (IL-1, IL-2, IL-4, IL-6, IL-8, IL-10), MCP-1, and NSE collectively contribute to the complex pathogenesis of lung cancer by influencing tumor growth, immune evasion, angiogenesis, and metastatic progression. Pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α promote tumor proliferation, survival, and angiogenesis, whereas immunomodulatory cytokines like IL-10 and IFN-γ regulate the TME, often enabling immune escape. Chemokines such as MCP-1 facilitate recruitment of monocytes and tumor-associated macrophages, further enhancing tumor progression. Meanwhile, tumor markers including CEA, CYFRA 21-1, SCC antigen, and NSE are widely used for diagnosis, prognosis, and monitoring therapeutic response. Future research should prioritize the development of integrated multi-biomarker panels that combine cytokines with established tumor markers to enhance early detection, diagnostic specificity, and prognostic precision in lung cancer. Additionally, there is a critical need to advance cytokine-targeted therapeutic strategies, particularly those aimed at inhibiting key pro-tumorigenic mediators such as IL-6, IL-8, and TNF-α, to attenuate inflammation-driven tumor progression. Further investigations should explore immunomodulatory approaches designed to restore effective anti-tumor immune responses through the regulation of IL-10 and IFN-γ signaling pathways. Comprehensive TME profiling is also essential to elucidate complex cytokine networks and to identify patient-specific molecular targets, thereby facilitating precision medicine approaches. Moreover, large-scale, longitudinal clinical studies are required to validate cytokine signatures as robust, non-invasive biomarkers for early screening, disease monitoring, and therapeutic response assessment. Finally, future efforts should emphasize combination treatment strategies, integrating cytokine-based interventions with immunotherapy, chemotherapy, and targeted therapies to improve overall treatment efficacy and to overcome therapeutic resistance. Overall, cytokines and tumor-associated biomarkers represent promising tools for advancing personalized diagnostics and therapeutics in lung cancer, though further validation and clinical translation remain essential.
| 1. | Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer. 2014;14:535-546. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 1023] [Cited by in RCA: 1492] [Article Influence: 124.3] [Reference Citation Analysis (16)] |
| 2. | Lan T, Chen L, Wei X. Inflammatory Cytokines in Cancer: Comprehensive Understanding and Clinical Progress in Gene Therapy. Cells. 2021;10:100. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 101] [Cited by in RCA: 161] [Article Influence: 32.2] [Reference Citation Analysis (4)] |
| 3. | Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 2021;27:1345-1356. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 897] [Cited by in RCA: 758] [Article Influence: 151.6] [Reference Citation Analysis (0)] |
| 4. | Essogmo FE, Zhilenkova AV, Tchawe YSN, Owoicho AM, Rusanov AS, Boroda A, Pirogova YN, Sangadzhieva ZD, Sanikovich VD, Bagmet NN, Sekacheva MI. Cytokine Profile in Lung Cancer Patients: Anti-Tumor and Oncogenic Cytokines. Cancers (Basel). 2023;15:5383. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 19] [Reference Citation Analysis (0)] |
| 5. | Liu H, Zhou C, Jiang H, Chu T, Zhong R, Zhang X, Shen Y, Han B. Prognostic role of serum cytokines level in non-small cell lung cancer patients with anti-PD-1 and chemotherapy combined treatment. Front Immunol. 2024;15:1430301. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 7] [Reference Citation Analysis (0)] |
| 6. | Bastawisy AE, Azzouny ME, Mohammed G, Allah AA, Behiry E. Serum cytokeratin 19 fragment in advanced lung cancer: could we eventually have a serum tumor marker? Ecancermedicalscience. 2014;8:394. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 4] [Reference Citation Analysis (0)] |
| 7. | Zhang YN, Jiang T, Zhang PJ, Wang HJ. Construction and validation of a multiparameter diagnostic model based on conventional tumor markers and cytokines for lung cancer. World J Clin Oncol. 2026;17:119365. [RCA] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 1] [Reference Citation Analysis (0)] |
| 8. | Hu S, Guo Q, Ye J, Ma H, Zhang M, Wang Y, Wan B, Qiu S, Liu X, Luo G, Zhang W, Yu D, Xu J, Wei Y, Zeng L. Development and validation of a tumor marker-based model for the prediction of lung cancer: an analysis of a multicenter retrospective study in Shanghai, China. Front Oncol. 2024;14:1427170. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 2] [Reference Citation Analysis (0)] |
| 9. | Hammarström S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol. 1999;9:67-81. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 1026] [Cited by in RCA: 923] [Article Influence: 34.2] [Reference Citation Analysis (4)] |
| 10. | Hao C, Zhang G, Zhang L. Serum CEA levels in 49 different types of cancer and noncancer diseases. Prog Mol Biol Transl Sci. 2019;162:213-227. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 48] [Cited by in RCA: 116] [Article Influence: 16.6] [Reference Citation Analysis (0)] |
| 11. | Yang Y, Xu M, Huang H, Jiang X, Gong K, Liu Y, Kuang X, Yang X. Serum carcinoembryonic antigen elevation in benign lung diseases. Sci Rep. 2021;11:19044. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 27] [Cited by in RCA: 38] [Article Influence: 7.6] [Reference Citation Analysis (0)] |
| 12. | Milner-Watts C, Minchom A, Bhosle J, Popat S, Tokaca N, Yousaf N, John A, McMahon D, O’Brien M, Davidson M. 1 Carcinoembryonic Antigen (CEA) monitoring in patients receiving systemic anti-cancer therapy (SACT) for advanced lung adenocarcinoma. Lung Cancer. 2026;212:108951. [DOI] [Full Text] |
| 13. | Lei J, Wu L, Zhang N, Liu X, Zhang J, Kuang L, Chen J, Chen Y, Li D, Li Y. Carcinoembryonic antigen potentiates non-small cell lung cancer progression via PKA-PGC-1ɑ axis. Mol Biomed. 2024;5:19. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 11] [Reference Citation Analysis (0)] |
| 14. | Enz N, Fragoso F, Gamrekeli A, Lippek F, Jungraithmayr W. Carcinoembryonic antigen-positive pleural effusion in early stage non-small cell lung cancer without pleural infiltration. J Thorac Dis. 2018;10:E340-E343. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 4] [Cited by in RCA: 8] [Article Influence: 1.0] [Reference Citation Analysis (0)] |
| 15. | Berezowska S, Maillard M, Keyter M, Bisig B. Pulmonary squamous cell carcinoma and lymphoepithelial carcinoma - morphology, molecular characteristics and differential diagnosis. Histopathology. 2024;84:32-49. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 1] [Cited by in RCA: 19] [Article Influence: 9.5] [Reference Citation Analysis (0)] |
| 16. | Drilon A, Rekhtman N, Ladanyi M, Paik P. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol. 2012;13:e418-e426. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 133] [Cited by in RCA: 149] [Article Influence: 10.6] [Reference Citation Analysis (0)] |
| 17. | Mizuguchi S, Nishiyama N, Iwata T, Nishida T, Izumi N, Tsukioka T, Inoue K, Kameyama M, Suehiro S. Clinical value of serum cytokeratin 19 fragment and sialyl-Lewis x in non-small cell lung cancer. Ann Thorac Surg. 2007;83:216-221. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 26] [Cited by in RCA: 26] [Article Influence: 1.4] [Reference Citation Analysis (0)] |
| 18. | Pastor A, Menéndez R, Cremades MJ, Pastor V, Llopis R, Aznar J. Diagnostic value of SCC, CEA and CYFRA 21.1 in lung cancer: a Bayesian analysis. Eur Respir J. 1997;10:603-609. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 2] [Cited by in RCA: 4] [Article Influence: 0.1] [Reference Citation Analysis (0)] |
| 19. | Fujita J, Ohtsuki Y, Bandoh S, Takashima H, Ueda Y, Wu F, Tojo Y, Kubo A, Ishida T. Elevation of cytokeratin 19 fragment (CYFRA 21-1) in serum of patients with radiation pneumonitis: possible marker of epithelial cell damage. Respir Med. 2004;98:294-300. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 13] [Cited by in RCA: 20] [Article Influence: 0.9] [Reference Citation Analysis (0)] |
| 20. | Kashiwabara K, Nakamura H, Esaki T. Serum cytokeratin 19 fragment levels in non-small cell lung cancer patients according to T factor in the TNM classification. Clin Chim Acta. 1999;288:153-159. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 1] [Cited by in RCA: 1] [Article Influence: 0.0] [Reference Citation Analysis (0)] |
| 21. | Gao J, Lv F, Li J, Wu Z, Qi J. Serum cytokeratin 19 fragment, CK19-2G2, as a newly identified biomarker for lung cancer. PLoS One. 2014;9:e101979. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 2] [Cited by in RCA: 10] [Article Influence: 0.8] [Reference Citation Analysis (0)] |
| 22. | Dohmoto K, Hojo S, Fujita J, Yang Y, Ueda Y, Bandoh S, Yamaji Y, Ohtsuki Y, Dobashi N, Ishida T, Takahara J. The role of caspase 3 in producing cytokeratin 19 fragment (CYFRA21-1) in human lung cancer cell lines. Int J Cancer. 2001;91:468-473. [PubMed] [DOI] [Full Text] |
| 23. | Benoot T, Piccioni E, De Ridder K, Goyvaerts C. TNFα and Immune Checkpoint Inhibition: Friend or Foe for Lung Cancer? Int J Mol Sci. 2021;22:8691. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 4] [Cited by in RCA: 35] [Article Influence: 7.0] [Reference Citation Analysis (0)] |
| 24. | Gong K, Guo G, Beckley N, Zhang Y, Yang X, Sharma M, Habib AA. Tumor necrosis factor in lung cancer: Complex roles in biology and resistance to treatment. Neoplasia. 2021;23:189-196. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 37] [Cited by in RCA: 55] [Article Influence: 11.0] [Reference Citation Analysis (0)] |
| 25. | Wang B, Song N, Yu T, Zhou L, Zhang H, Duan L, He W, Zhu Y, Bai Y, Zhu M. Expression of tumor necrosis factor-alpha-mediated genes predicts recurrence-free survival in lung cancer. PLoS One. 2014;9:e115945. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 9] [Cited by in RCA: 15] [Article Influence: 1.3] [Reference Citation Analysis (0)] |
| 26. | Uemura Y, Kobayashi M, Nakata H, Kubota T, Saito T, Bandobashi K, Taguchi H. Effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on lung cancer: roles of cyclooxygenase-2. Oncol Rep. 2007;17:955-961. [PubMed] |
| 27. | Tsuruta N, Yatsunami J, Takayama K, Nakanishi Y, Ichinose Y, Hara N. Granulocyte-macrophage-colony stimulating factor stimulates tumor invasiveness in squamous cell lung carcinoma. Cancer. 1998;82:2173-2183. [PubMed] |
| 28. | Park Y, Chung C. Immune Evasion of G-CSF and GM-CSF in Lung Cancer. Tuberc Respir Dis (Seoul). 2024;87:22-30. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 9] [Reference Citation Analysis (1)] |
| 29. | Kowanetz M, Wu X, Lee J, Tan M, Hagenbeek T, Qu X, Yu L, Ross J, Korsisaari N, Cao T, Bou-Reslan H, Kallop D, Weimer R, Ludlam MJ, Kaminker JS, Modrusan Z, van Bruggen N, Peale FV, Carano R, Meng YG, Ferrara N. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci U S A. 2010;107:21248-21255. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 432] [Cited by in RCA: 530] [Article Influence: 33.1] [Reference Citation Analysis (1)] |
| 30. | Cao Z, Meng Z, Li J, Tian Y, Lu L, Wang A, Huang J, Wang J, Sun J, Chen L, Lu S, Li Z. Interferon-γ-stimulated antigen-presenting cancer-associated fibroblasts hinder neoadjuvant chemoimmunotherapy efficacy in lung cancer. Cell Rep Med. 2025;6:102017. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 1] [Cited by in RCA: 16] [Article Influence: 16.0] [Reference Citation Analysis (0)] |
| 31. | Kratzmeier C, Taheri M, Mei Z, Lim I, Khalil MA, Carter-Cooper B, Fanaroff RE, Ong CS, Schneider EB, Chang S, Leyder E, Li D, Luzina IG, Banerjee A, Krupnick AS. Lung adenocarcinoma-derived IFN-γ promotes growth by modulating CD8+ T cell production of CCR5 chemokines. J Clin Invest. 2025;135:e191070. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 4] [Cited by in RCA: 6] [Article Influence: 6.0] [Reference Citation Analysis (0)] |
| 32. | Yin H, Jiang Z, Wang S, Zhang P. IFN-γ restores the impaired function of RNase L and induces mitochondria-mediated apoptosis in lung cancer. Cell Death Dis. 2019;10:642. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 7] [Cited by in RCA: 26] [Article Influence: 3.7] [Reference Citation Analysis (0)] |
| 33. | Yao B, Wang L, Wang H, Bao J, Li Q, Yu F, Zhu W, Zhang L, Li W, Gu Z, Fei K, Zhang P, Zhang F, Huang X. Seven interferon gamma response genes serve as a prognostic risk signature that correlates with immune infiltration in lung adenocarcinoma. Aging (Albany NY). 2021;13:11381-11410. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 22] [Cited by in RCA: 21] [Article Influence: 4.2] [Reference Citation Analysis (0)] |
| 34. | Qu S, Jiao Z, Lu G, Xu J, Yao B, Wang T, Wang J, Yao Y, Yan X, Wang T, Liang H, Zen K. Human lung adenocarcinoma CD47 is upregulated by interferon-γ and promotes tumor metastasis. Mol Ther Oncolytics. 2022;25:276-287. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 1] [Cited by in RCA: 15] [Article Influence: 3.8] [Reference Citation Analysis (0)] |
| 35. | Garon EB, Chih-Hsin Yang J, Dubinett SM. The Role of Interleukin 1β in the Pathogenesis of Lung Cancer. JTO Clin Res Rep. 2020;1:100001. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 23] [Cited by in RCA: 38] [Article Influence: 6.3] [Reference Citation Analysis (0)] |
| 36. | Tan Q, Duan L, Huang Q, Chen W, Yang Z, Chen J, Jin Y. Interleukin -1β Promotes Lung Adenocarcinoma Growth and Invasion Through Promoting Glycolysis via p38 Pathway. J Inflamm Res. 2021;14:6491-6509. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 23] [Cited by in RCA: 20] [Article Influence: 4.0] [Reference Citation Analysis (0)] |
| 37. | Yano T, Fukuyama Y, Yokoyama H, Takai E, Tanaka Y, Asoh H, Ichinose Y. Interleukin-2 receptors in pulmonary adenocarcinoma tissue. Lung Cancer. 1996;16:13-19. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 18] [Cited by in RCA: 19] [Article Influence: 0.6] [Reference Citation Analysis (0)] |
| 38. | Hou Y, Xiang B, Yang Z, Liu J, Xu D, Geng L, Zhan M, Xu Y, Zhang B. Down-regulation of interleukin-2 predicts poor prognosis and associated with immune escape in lung adenocarcinoma. Int J Immunopathol Pharmacol. 2023;37:3946320231202748. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 5] [Reference Citation Analysis (0)] |
| 39. | Rodriguez-Tirado C, Entenberg D, Li J, Qian BZ, Condeelis JS, Pollard JW. Interleukin 4 Controls the Pro-Tumoral Role of Macrophages in Mammary Cancer Pulmonary Metastasis in Mice. Cancers (Basel). 2022;14:4336. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 12] [Cited by in RCA: 29] [Article Influence: 7.3] [Reference Citation Analysis (0)] |
| 40. | Qu Z, Sun F, Zhou J, Li L, Shapiro SD, Xiao G. Interleukin-6 Prevents the Initiation but Enhances the Progression of Lung Cancer. Cancer Res. 2015;75:3209-3215. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 58] [Cited by in RCA: 85] [Article Influence: 7.7] [Reference Citation Analysis (2)] |
| 41. | Tang H, Zhang Y, Zhao S, Song C. Common mechanisms involved in lung cancer and depression: The dominant role of interleukin-6-IDO pathway in the lung-brain axis. J Affect Disord Rep. 2023;12:100580. [RCA] [DOI] [Full Text] [Cited by in RCA: 3] [Reference Citation Analysis (0)] |
| 42. | Santoso A, Rasiha R, Munawwarah S, Mustang A. The Role of Interleukin 6 and Cyclooxygenase 2 In Progressivity and Metastatic Process in Andavce Non Small Cell Lung Cancer. Eur Respir J. 2022;60:4316. [DOI] [Full Text] |
| 43. | An J, Gu Q, Cao L, Yang H, Deng P, Hu C, Li M. Serum IL-6 as a vital predictor of severe lung cancer. Ann Palliat Med. 2021;10:202-209. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 2] [Cited by in RCA: 20] [Article Influence: 4.0] [Reference Citation Analysis (0)] |
| 44. | Zhu YM, Webster SJ, Flower D, Woll PJ. Interleukin-8/CXCL8 is a growth factor for human lung cancer cells. Br J Cancer. 2004;91:1970-1976. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 201] [Cited by in RCA: 194] [Article Influence: 8.8] [Reference Citation Analysis (0)] |
| 45. | Favaro F, Luciano-Mateo F, Moreno-Caceres J, Hernández-Madrigal M, Both D, Montironi C, Püschel F, Nadal E, Eldering E, Muñoz-Pinedo C. TRAIL receptors promote constitutive and inducible IL-8 secretion in non-small cell lung carcinoma. Cell Death Dis. 2022;13:1046. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 35] [Reference Citation Analysis (0)] |
| 46. | Li CH, Yang YC, Hsia TC, Shen TC, Shen YC, Chang WS, Wang YC, Tsai CW, Bau DT. Association of Interleukin-8 Promoter Genotypes With Taiwan Lung Cancer Risk. Anticancer Res. 2022;42:1229-1236. [RCA] [PubMed] [DOI] [Full Text] [Reference Citation Analysis (0)] |
| 47. | Luppi F, Longo AM, de Boer WI, Rabe KF, Hiemstra PS. Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation. Lung Cancer. 2007;56:25-33. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 150] [Cited by in RCA: 171] [Article Influence: 8.6] [Reference Citation Analysis (3)] |
| 48. | Hsu TI, Wang YC, Hung CY, Yu CH, Su WC, Chang WC, Hung JJ. Positive feedback regulation between IL10 and EGFR promotes lung cancer formation. Oncotarget. 2016;7:20840-20854. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 23] [Cited by in RCA: 34] [Article Influence: 4.3] [Reference Citation Analysis (0)] |
| 49. | Wang H, Zhou F, Zhao C, Cheng L, Zhou C, Qiao M, Li X, Chen X. Interleukin-10 Is a Promising Marker for Immune-Related Adverse Events in Patients With Non-Small Cell Lung Cancer Receiving Immunotherapy. Front Immunol. 2022;13:840313. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 4] [Cited by in RCA: 35] [Article Influence: 8.8] [Reference Citation Analysis (0)] |
| 50. | Vahl JM, Friedrich J, Mittler S, Trump S, Heim L, Kachler K, Balabko L, Fuhrich N, Geppert CI, Trufa DI, Sopel N, Rieker R, Sirbu H, Finotto S. Interleukin-10-regulated tumour tolerance in non-small cell lung cancer. Br J Cancer. 2017;117:1644-1655. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 51] [Cited by in RCA: 82] [Article Influence: 9.1] [Reference Citation Analysis (0)] |
| 51. | Lan X, Lan T, Faxiang Q. Interleukin-10 promoter polymorphism and susceptibility to lung cancer: a systematic review and meta-analysis. Int J Clin Exp Med. 2015;8:15317-15328. [PubMed] |
| 52. | Soria JC, Moon C, Kemp BL, Liu DD, Feng L, Tang X, Chang YS, Mao L, Khuri FR. Lack of interleukin-10 expression could predict poor outcome in patients with stage I non-small cell lung cancer. Clin Cancer Res. 2003;9:1785-1791. [PubMed] |
| 53. | Fridlender ZG, Kapoor V, Buchlis G, Cheng G, Sun J, Wang LC, Singhal S, Snyder LA, Albelda SM. Monocyte chemoattractant protein-1 blockade inhibits lung cancer tumor growth by altering macrophage phenotype and activating CD8+ cells. Am J Respir Cell Mol Biol. 2011;44:230-237. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 101] [Cited by in RCA: 131] [Article Influence: 8.2] [Reference Citation Analysis (0)] |
| 54. | Shih CM, Lee YL. Association of the Monocyte Chemoattractant Protein 1 and Chemokine Receptor 2 Genetic Polymorphisms with Non-small Cell Lung Cancer in Taiwan. Eur Respir J. 2017;50:PA2041. [RCA] [DOI] [Full Text] [Cited by in RCA: 1] [Reference Citation Analysis (0)] |
| 55. | Cai Z, Chen Q, Chen J, Lu Y, Xiao G, Wu Z, Zhou Q, Zhang J. Monocyte chemotactic protein 1 promotes lung cancer-induced bone resorptive lesions in vivo. Neoplasia. 2009;11:228-236. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 63] [Cited by in RCA: 67] [Article Influence: 3.9] [Reference Citation Analysis (0)] |
| 56. | Zhang XW, Qin X, Qin CY, Yin YL, Chen Y, Zhu HL. Expression of monocyte chemoattractant protein-1 and CC chemokine receptor 2 in non-small cell lung cancer and its significance. Cancer Immunol Immunother. 2013;62:563-570. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 28] [Cited by in RCA: 35] [Article Influence: 2.7] [Reference Citation Analysis (0)] |
| 57. | Ekekezie II, Thibeault DW, Garola RE, Truog WE. Monocyte chemoattractant protein-1 and its receptor CCR-2 in piglet lungs exposed to inhaled nitric oxide and hyperoxia. Pediatr Res. 2001;50:633-640. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 9] [Cited by in RCA: 10] [Article Influence: 0.4] [Reference Citation Analysis (0)] |
| 58. | Yoshimura T, Howard OM, Ito T, Kuwabara M, Matsukawa A, Chen K, Liu Y, Liu M, Oppenheim JJ, Wang JM. Monocyte chemoattractant protein-1/CCL2 produced by stromal cells promotes lung metastasis of 4T1 murine breast cancer cells. PLoS One. 2013;8:e58791. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 65] [Cited by in RCA: 89] [Article Influence: 6.8] [Reference Citation Analysis (1)] |
| 59. | Xu CM, Luo YL, Li S, Li ZX, Jiang L, Zhang GX, Owusu L, Chen HL. Multifunctional neuron-specific enolase: its role in lung diseases. Biosci Rep. 2019;39:BSR20192732. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 26] [Cited by in RCA: 79] [Article Influence: 13.2] [Reference Citation Analysis (0)] |
| 60. | Xu FZ, Zhang YB. Correlation analysis between serum neuron-specific enolase and the detection of gene mutations in lung adenocarcinoma. J Thorac Dis. 2021;13:552-561. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 2] [Cited by in RCA: 4] [Article Influence: 0.8] [Reference Citation Analysis (0)] |
| 61. | Lu L, Zha Z, Zhang P, Wang P, Liu X, Fang X, Weng C, Li B, Mao H, Wang L, Guan M, Wu Y, Xu Z, Liu Z, Liu G. Neuron-specific enolase promotes stem cell-like characteristics of small-cell lung cancer by downregulating NBL1 and activating the BMP2/Smad/ID1 pathway. Oncogenesis. 2022;11:21. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 19] [Reference Citation Analysis (0)] |
| 62. | Reeve JG, Stewart J, Watson JV, Wulfrank D, Twentyman PR, Bleehen NM. Neuron specific enolase expression in carcinoma of the lung. Br J Cancer. 1986;53:519-528. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 19] [Cited by in RCA: 22] [Article Influence: 0.6] [Reference Citation Analysis (0)] |
| 63. | Karnak D, Beder S, Kayacan O, Ibiş E, Oflaz G. Neuron-specific enolase and lung cancer. Am J Clin Oncol. 2005;28:586-590. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 12] [Cited by in RCA: 12] [Article Influence: 0.6] [Reference Citation Analysis (0)] |
| 64. | Li L, Xu Y, Wang Y, Zhang Q, Wang Y, Xu C. The Diagnostic and Prognostic Value of the Combination of Tumor M2-Pyruvate Kinase, Carcinoembryonic Antigen, and Cytokeratin 19 Fragment in Non-Small Cell Lung Cancer. Technol Cancer Res Treat. 2024;23:15330338241265983. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 1] [Cited by in RCA: 3] [Article Influence: 1.5] [Reference Citation Analysis (0)] |
| 65. | Shang GS, Liu L, Qin YW. IL-6 and TNF-α promote metastasis of lung cancer by inducing epithelial-mesenchymal transition. Oncol Lett. 2017;13:4657-4660. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 47] [Cited by in RCA: 103] [Article Influence: 11.4] [Reference Citation Analysis (0)] |
| 66. | Boldrini L, Gisfredi S, Ursino S, Lucchi M, Melfi F, Mussi A, Basolo F, Fontanini G. Tumour necrosis factor-alpha: prognostic role and relationship with interleukin-8 and endothelin-1 in non-small cell lung cancer. Int J Mol Med. 2006;17:887-892. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 1] [Cited by in RCA: 1] [Article Influence: 0.1] [Reference Citation Analysis (0)] |
| 67. | Zhang Y, Zhu K, Wang X, Zhao Y, Shi J, Liu Z. Roles of IL-4, IL-13, and Their Receptors in Lung Cancer. J Interferon Cytokine Res. 2024;44:399-407. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 2] [Cited by in RCA: 11] [Article Influence: 5.5] [Reference Citation Analysis (0)] |
| 68. | Arrieta O, Villarreal-Garza C, Martínez-Barrera L, Morales M, Dorantes-Gallareta Y, Peña-Curiel O, Contreras-Reyes S, Macedo-Pérez EO, Alatorre-Alexander J. Usefulness of serum carcinoembryonic antigen (CEA) in evaluating response to chemotherapy in patients with advanced non small-cell lung cancer: a prospective cohort study. BMC Cancer. 2013;13:254. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 33] [Cited by in RCA: 58] [Article Influence: 4.5] [Reference Citation Analysis (0)] |
| 69. | Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer. 2012;76:138-143. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 618] [Cited by in RCA: 533] [Article Influence: 38.1] [Reference Citation Analysis (0)] |
| 70. | Takada M, Masuda N, Matsuura E, Kusunoki Y, Matui K, Nakagawa K, Yana T, Tuyuguchi I, Oohata I, Fukuoka M. Measurement of cytokeratin 19 fragments as a marker of lung cancer by CYFRA 21-1 enzyme immunoassay. Br J Cancer. 1995;71:160-165. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 53] [Cited by in RCA: 54] [Article Influence: 1.7] [Reference Citation Analysis (0)] |
| 71. | Wylam ME, Ten R, Prakash UB, Nadrous HF, Clawson ML, Anderson PM. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J. 2006;27:585-593. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 85] [Cited by in RCA: 76] [Article Influence: 3.8] [Reference Citation Analysis (0)] |
| 72. | Pogrebniak HW, Prewitt TW, Matthews WA, Pass HI. Tumor necrosis factor-alpha alters response of lung cancer cells to oxidative stress. J Thorac Cardiovasc Surg. 1991;102:904-907. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 8] [Cited by in RCA: 11] [Article Influence: 0.3] [Reference Citation Analysis (0)] |
| 73. | Alhawmdeh M, Isreb M, Aziz A, Jacob BK, Anderson D, Najafzadeh M. Interferon-γ liposome: a new system to improve drug delivery in the treatment of lung cancer. ERJ Open Res. 2021;7:00555-02020. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 11] [Cited by in RCA: 8] [Article Influence: 1.6] [Reference Citation Analysis (0)] |
| 74. | Lee KS, Chung WY, Park JE, Jung YJ, Park JH, Sheen SS, Park KJ. Interferon-γ-Inducible Chemokines as Prognostic Markers for Lung Cancer. Int J Environ Res Public Health. 2021;18:9345. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 14] [Reference Citation Analysis (0)] |
| 75. | Tang M, Yin Y, Wang W, Gong K, Dong J, Gao X, Li J, Fang L, Ma J, Hong Y, Li Z, Bi T, Zhang W, Liu W. Exploring the multifaceted effects of Interleukin-1 in lung cancer: From tumor development to immune modulation. Life Sci. 2024;342:122539. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 7] [Cited by in RCA: 8] [Article Influence: 4.0] [Reference Citation Analysis (0)] |
| 76. | Zhang J, Veeramachaneni N. Targeting interleukin-1β and inflammation in lung cancer. Biomark Res. 2022;10:5. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 49] [Cited by in RCA: 62] [Article Influence: 15.5] [Reference Citation Analysis (0)] |
| 77. | Perrichet A, Lecuelle J, Limagne E, Thiefin M, Bellio H, Jacob P, Aucagne R, Aznague A, Russo P, Gaucher F, Roussot N, Yang X, Vernet T, Nuttin L, Ilie A, Rageot D, Derangère V, Huppe T, Zippelius A, Routy B, Truntzer C, Chalmin F, Ghiringhelli F, Rébé C. Cancer cell-derived IL-1β reverses chemo-immunotherapy resistance in non-small cell lung cancer. Nat Commun. 2025;16:10244. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 4] [Reference Citation Analysis (0)] |
| 78. | Yuan B, Clowers MJ, Velasco WV, Peng S, Peng Q, Shi Y, Ramos-Castaneda M, Zarghooni M, Yang S, Babcock RL, Chang SH, Heymach JV, Zhang J, Ostrin EJ, Watowich SS, Kadara H, Moghaddam SJ. Targeting IL-1β as an immunopreventive and therapeutic modality for K-ras-mutant lung cancer. JCI Insight. 2022;7:e157788. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 78] [Cited by in RCA: 67] [Article Influence: 16.8] [Reference Citation Analysis (0)] |
| 79. | Clamon G, Herndon J, Perry MC, Ozer H, Kreisman H, Maher T, Ellerton J, Green MR. Interleukin-2 activity in patients with extensive small-cell lung cancer: a phase II trial of Cancer and Leukemia Group B. J Natl Cancer Inst. 1993;85:316-320. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 26] [Cited by in RCA: 23] [Article Influence: 0.7] [Reference Citation Analysis (0)] |
| 80. | Orditura M, Romano C, De Vita F, Galizia G, Lieto E, Infusino S, De Cataldis G, Catalano G. Behaviour of interleukin-2 serum levels in advanced non-small-cell lung cancer patients: relationship with response to therapy and survival. Cancer Immunol Immunother. 2000;49:530-536. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 42] [Cited by in RCA: 36] [Article Influence: 1.4] [Reference Citation Analysis (0)] |
| 81. | Kawakami M, Kawakami K, Stepensky VA, Maki RA, Robin H, Muller W, Husain SR, Puri RK. Interleukin 4 receptor on human lung cancer: a molecular target for cytotoxin therapy. Clin Cancer Res. 2002;8:3503-3511. [PubMed] |
| 82. | Chang WS, Wang SC, Chuang CL, Ji HX, Hsiao CL, Hsu CM, Tsai CW, Liu SP, Hsu PC, Lo YL, Bau DT. Contribution of Interleukin-4 Genotypes to Lung Cancer Risk in Taiwan. Anticancer Res. 2015;35:6297-6301. [PubMed] |
| 83. | Topp MS, Koenigsmann M, Mire-Sluis A, Oberberg D, Eitelbach F, von Marschall Z, Notter M, Reufi B, Stein H, Thiel E. Recombinant human interleukin-4 inhibits growth of some human lung tumor cell lines in vitro and in vivo. Blood. 1993;82:2837-2844. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 39] [Cited by in RCA: 33] [Article Influence: 1.0] [Reference Citation Analysis (0)] |
| 84. | Newnes HV, Armitage JD, Buzzai AC, de Jong E, Audsley KM, Barnes SA, Srinivasan S, Serralha M, Fear VS, Guo BB, Jones ME, Forrest ARR, Foley B, Darcy PK, Beavis PA, Bosco A, Waithman J. Interleukin-4 modulates type I interferon to augment antitumor immunity. Sci Adv. 2025;11:eadt3618. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 6] [Reference Citation Analysis (0)] |
| 85. | Khilwani R, Singh S. Leveraging Evolutionary Immunology in Interleukin-6 and Interleukin-17 Signaling for Lung Cancer Therapeutics. ACS Pharmacol Transl Sci. 2024;7:3658-3670. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 3] [Reference Citation Analysis (0)] |
| 86. | Ke W, Zhang L, Dai Y. The role of IL-6 in immunotherapy of non-small cell lung cancer (NSCLC) with immune-related adverse events (irAEs). Thorac Cancer. 2020;11:835-839. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 20] [Cited by in RCA: 51] [Article Influence: 8.5] [Reference Citation Analysis (0)] |
| 87. | Wang Y, Liu C, Yang L, Xu H, Sun N. 1304P Interleukin-6 (IL-6) as a potential predictive marker and a desensitizer for immunotherapy response in non-small cell lung cancer. Ann Oncol. 2021;32:S1007-S1008. [RCA] [DOI] [Full Text] [Cited by in RCA: 1] [Reference Citation Analysis (0)] |
| 88. | Belluomini L, Cesta Incani U, Smimmo A, Avancini A, Sposito M, Insolda J, Mariangela Scaglione I, Gattazzo F, Caligola S, Adamo A, Conciatori F, Bazzichetto C, Ugel S, Giannarelli D, Pilotto S, Milella M. Prognostic impact of Interleukin-8 levels in lung cancer: A meta-analysis and a bioinformatic validation. Lung Cancer. 2024;194:107893. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 10] [Cited by in RCA: 9] [Article Influence: 4.5] [Reference Citation Analysis (0)] |
| 89. | Wang J, Huang M, Lee P, Komanduri K, Sharma S, Chen G, Dubinett SM. Interleukin-8 inhibits non-small cell lung cancer proliferation: a possible role for regulation of tumor growth by autocrine and paracrine pathways. J Interferon Cytokine Res. 1996;16:53-60. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 39] [Cited by in RCA: 40] [Article Influence: 1.3] [Reference Citation Analysis (0)] |
| 90. | Ramos C, Gerstenberg A, Boute M, Lapage M. Dual analysis of IL-8 in non-small cell lung cancer: A clinical perspective on protein and RNA evaluation via imaging mass cytometry. J Clin Oncol. 2024;42:e15068. [DOI] [Full Text] |
| 91. | Meier C, Brieger A. The role of IL-8 in cancer development and its impact on immunotherapy resistance. Eur J Cancer. 2025;218:115267. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 36] [Cited by in RCA: 37] [Article Influence: 37.0] [Reference Citation Analysis (0)] |
| 92. | Hatanaka H, Abe Y, Kamiya T, Morino F, Nagata J, Tokunaga T, Oshika Y, Suemizu H, Kijima H, Tsuchida T, Yamazaki H, Inoue H, Nakamura M, Ueyama Y. Clinical implications of interleukin (IL)-10 induced by non-small-cell lung cancer. Ann Oncol. 2000;11:815-819. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 57] [Cited by in RCA: 68] [Article Influence: 2.6] [Reference Citation Analysis (0)] |
| 93. | Friedrich J, Kroß B, Trump S, Holzinger C, Finotto S. The Role of Interleukin (IL) - 10 in a murine model of lung adenocarcinoma (ADC). Eur Respir J. 2017;50:PA4207. [RCA] [DOI] [Full Text] [Cited by in RCA: 1] [Reference Citation Analysis (0)] |
| 94. | Sung WW, Lee H. The role of interleukin-10 in the progression of human papillomavirus-associated lung carcinoma. Oncoimmunology. 2013;2:e25854. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 13] [Cited by in RCA: 17] [Article Influence: 1.3] [Reference Citation Analysis (0)] |
| 95. | Izaguirre-Alvarez JM, Zapata-Benavides P, Arellano-Rodríguez M, Arellano-Rodríguez NC, Torres-Del-Muro FD, Franco-Molina MA, Rodríguez-Padilla MC. Cytokine-driven modulation of WT1 and IL-10 in lung cancer progression. Transl Lung Cancer Res. 2025;14:1896-1913. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 1] [Reference Citation Analysis (0)] |
| 96. | Nokihara H, Nishioka Y, Yano S, Mukaida N, Matsushima K, Tsuruo T, Sone S. Monocyte chemoattractant protein-1 gene modification of multidrug-resistant human lung cancer enhances antimetastatic effect of therapy with anti-P-glycoprotein antibody in SCID mice. Int J Cancer. 1999;80:773-780. [PubMed] [DOI] [Full Text] |
| 97. | Wu Y, Tang Y, Huang W, Zhu C, Ju H, Wu J, Zhang Q, Zhao Y, Kong H. Improving the screening ability of neuron-specific enolase on small cell lung cancer. Lung Cancer. 2025;199:108078. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 5] [Cited by in RCA: 3] [Article Influence: 3.0] [Reference Citation Analysis (0)] |
| 98. | Bonner JA, Sloan JA, Rowland KM Jr, Klee GG, Kugler JW, Mailliard JA, Wiesenfeld M, Krook JE, Maksymiuk AW, Shaw EG, Marks RS, Perez EA. Significance of neuron-specific enolase levels before and during therapy for small cell lung cancer. Clin Cancer Res. 2000;6:597-601. [PubMed] |
| 99. | Muley T, Rolny V, He Y, Wehnl B, Escherich A, Warth A, Stolp C, Schneider MA, Dienemann H, Meister M, Herth FJ, Dayyani F. The combination of the blood based tumor biomarkers cytokeratin 19 fragments (CYFRA 21-1) and carcinoembryonic antigen (CEA) as a potential predictor of benefit from adjuvant chemotherapy in early stage squamous cell carcinoma of the lung (SCC). Lung Cancer. 2018;120:46-53. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 15] [Cited by in RCA: 19] [Article Influence: 2.4] [Reference Citation Analysis (0)] |
| 100. | Rowe DJ, Khalil TA, Kammer MN, Godfrey CM, Zou Y, Vnencak-Jones CL, Xiao D, Deppen S, Grogan EL. A deeper evaluation of cytokeratin fragment 21-1 as a lung cancer tumor marker and comparison of different assays. Biosens Bioelectron X. 2025;23:100593. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 3] [Reference Citation Analysis (0)] |
| 101. | Johnson DH. Granulocyte colony-stimulating factor in lung cancer. Lung Cancer. 1993;9:35-43. [RCA] [DOI] [Full Text] [Cited by in Crossref: 2] [Cited by in RCA: 3] [Article Influence: 0.1] [Reference Citation Analysis (0)] |
| 102. | Hu D, Zhang Y, Cao R, Hao Y, Yang X, Tian T, Zhang J. The protective effects of granulocyte-macrophage colony-stimulating factor against radiation-induced lung injury. Transl Lung Cancer Res. 2020;9:2440-2459. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 2] [Cited by in RCA: 13] [Article Influence: 2.6] [Reference Citation Analysis (0)] |
| 103. | Lau SCM, Pan Y, Velcheti V, Wong KK. Squamous cell lung cancer: Current landscape and future therapeutic options. Cancer Cell. 2022;40:1279-1293. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 122] [Cited by in RCA: 133] [Article Influence: 33.3] [Reference Citation Analysis (0)] |
| 104. | Splinter TA, Cooper EH, Kho GS, Oosterom R, Peake MD. Neuron-specific enolase as a guide to the treatment of small cell lung cancer. Eur J Cancer Clin Oncol. 1987;23:171-176. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 34] [Cited by in RCA: 34] [Article Influence: 0.9] [Reference Citation Analysis (0)] |
| 105. | Davaajav K, Dagva D, Dashtseren I, Takahashi Y, Nakayama T. Elevated Levels of the Cancer Marker Neuron-Specific Enolase in a Patient With Coexisting Silicosis and Sarcoidosis. Cureus. 2024;16:e61130. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 2] [Reference Citation Analysis (0)] |
| 106. | Tan Z, Xue H, Sun Y, Zhang C, Song Y, Qi Y. The Role of Tumor Inflammatory Microenvironment in Lung Cancer. Front Pharmacol. 2021;12:688625. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 65] [Cited by in RCA: 155] [Article Influence: 31.0] [Reference Citation Analysis (1)] |