Lung carcinoma, also known as lung cancer, is a type of lung cancer that usually results from uncontrolled cell proliferation of the lungs. Tissues containing epithelial cells that have transformed into malignant cells are examples of lung cancer. Abnormal masses or nodules may be seen on chest X-rays [1]. A computerized tomography (CT) scan can also help to see small lung lesions that X-rays may have missed.

Lung cancer is currently the second leading cause of cancer worldwide. Although lung cancer can occur in people who have never smoked, people who smoke are the group most likely to develop lung cancer. Both the amount and frequency of smoking can affect a person’s risk of developing lung cancer. People who quit smoking after smoking for a long time will have a decreased risk of developing lung cancer [1].

To reduce the number of deaths from lung cancer, the best option is to increase the effectiveness of cancer prevention and to use screening strategies for risk assessment and detection in the early stages of lung cancer treatment [2]. According to a study by R. Kuner, the estimated number of new cases and deaths from lung cancer in the United States in 2013 was 228,190 and 159,480, respectively. Approximately 55% to 60% of patients have distant metastases and are diagnosed at an advanced, incurable stage. Therefore, the five-year overall survival rate of each stage is between 13% and 16% [3].

Non-small cell lung cancer, also known as NSCLC, is the most common type of bronchial malignancy. Adenocarcinoma and squamous cell carcinoma are the two main histological groups from which they are often separated. Adenocarcinoma and squamous carcinoma cells differ in DNA copy number, DNA methylation, gene mutations, transcriptome, proteome, and potential biomarkers [2].

In lung cancer, cytokines, or proteins, are important to support the immune system. They can promote tumor growth (oncogenic cytokines) or inhibit tumor growth (anti-tumor cytokines) by modulating related factors such as growth, proliferation, metastasis, and apoptosis [2].

Several cytokines restrict tumor cell growth through direct anti-proliferative or pro-apoptotic activites, or indirectly by stimulating the cytotoxic activity of immune cells against tumor cells. An example is interferon-alpha (IFN-α), which was first discovered in 1957 as a result of its antiviral properties. Thirteen years later, Gresser and Bourali described the anti-tumor activity of IFN-α against different tumor cell lines inoculated in mice ^[4][42]. The biggest challenge in the development of anti-cancer drugs is to target and kill only the cancer cells without harming the normal body cells. Interferons (IFNs) are naturally produced by people's body cells in response to pathological compromise, and these chemical messengers render the neighboring normal cells resistant to similar types of infection. Interferons regulate angiogenesis and have immunomodulatory capacities, and are hence a fantastic therapeutic choice against cancer ^[5][43]. Literature data have demonstrated that inhalation of asbestiform fibers can bring about various inter-connected pathogenetic lung diseases, represented by chronic inflammation and carcinogenesis. Previous investigations have analyzed fundamental pathologic changes following asbestos exposure, highlighting critical pathogenic pathways involving oxidative stress, apoptosis, and inflammation. In 1987, the International Agency for Research on Cancer (IARC) classified asbestos as a group 1 (definite) human carcinogen ^[6][44].

The interleukin-1 (IL-1) family is one of the first described cytokine families and is made up of eight cytokines (IL-1β, IL-1α, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, and IL-37) and three receptor antagonists (IL-1Ra, IL-36Ra, and IL-38). The IL-1 family members are known to play an important role in inflammation ^[7][45]. IL-1 is an important regulator in innate immunity, which can stimulate IFN-γ production by T cells and NK cells. IL-1 plays a dual role in the anticancer immune response. Clinically, patients with high IL-1 concentrations in tumors have poor prognoses ^[8][46]. IL-1β is a key mediator in the initiation of the inflammatory response in pulmonary diseases, including chronic obstructive pulmonary disease and lung cancer. Lung inflammation is characterized by macrophage infiltration and increased thickness and fibrosis of the airways, leading to airflow obstruction. IL-1β polymorphisms that lead to IL-1β upregulation may influence the level of reactive oxygen and nitrogen species in the lung epithelial microenvironment, which may invoke inflammatory-mediated induction of mutations in tumor suppressor genes such as TP53. Several strategies are being used to inhibit IL-1 signaling in human disease, including antibodies directed against IL-1α, IL-1β, and the IL-1 receptor. Anakinra, a recombinant version of the naturally occurring IL-1 receptor antagonist, is approved for the treatment of rheumatoid arthritis and cryopyrin-associated periodic syndromes (CAPS) ^[9][47].

Interleukin-2 (IL-2), also known as aldesleukin or PROLEUKIN^®, is considered to be an immunotherapy treatment for people with metastatic melanoma. IL-2 is a naturally occurring protein that is produced by T lymphocytes. Its normal function in the body is to increase the growth and activity of other white blood cells (T and B lymphocytes). When IL-2 is used for cancer therapy, it is manufactured into a product called aldesleukin; a drug used to boost the immune system to fight cancer cells ^[10][48]. IL-2 alone or in combination with other anti-cancer therapies has brought some survival benefits to advanced cancer patients. A recent meta-analysis seems to support the use of IL-2 in combination with chemotherapy in solid tumors other than melanoma and renal cancer, reporting a trend toward better prognosis in the response in several solid tumors. Another meta-analysis also shows that IL-2 combination therapy is efficacious in treating non-small cell lung cancer, improves overall survival, and did not show significant toxic reactions. In China, IL-2 has been approved for the treatment of malignant pleural effusion (MPE) since 1998. In subsequent years, some randomized controlled trials (RCTs) have specially explored the clinical efficacy and safety of IL-2 combined with cisplatin versus cisplatin alone in treating MPE through thoracic injection ^[11][49].

Interleukin-3 (IL-3) cytokines bind to a receptor made up of a unique IL-3Rα subunit and the common βc subunit. They synergize with other cytokines to stimulate the growth of immature progenitor cells of all lineages, and are therefore known to be a multi-lineage colony-stimulating factor (CSF) ^[12][50]. They are equally known to be a multipotent hematopoietic growth factor which is produced by activated T-cells, monocytes/macrophages, and stroma cells. Human IL-3 genes are shown to be located on chromosome 5 near segment 5q31 ^[13][51]. Interleukin 3 is an interleukin, a type of biological signal that can improve the body’s natural immune response to disease as part of the immune system. IL-3 works to regulate the inflammatory response in order to clear pathogens by changing the abundance of various cell populations via binding at the interleukin-3 receptor ^[14][52].

Interleukin-4 (IL-4) is a multifunctional cytokine which plays an important role in immune response regulation and is involved in various processes associated with the development and differentiation of lymphocytes and the regulation of T cell survival ^[15][53]. IL-4 is mainly required for lineage-specific differentiation of Th2 cells and regulation of humoral immune responses. In addition to basophils and mast cells, IL-4 is predominantly secreted by Th2 cells via autocrine signaling. It plays multiple roles in the tumor microenvironment and exhibits immune-suppressive and antitumor activities ^[16][54]. IL-4 could also promote the proliferation and survival of several cancer cells. It was found to be over expressed by many human tumor types, including malignant glioma, ovarian, lung, breast, pancreatic, colon, and bladder carcinomas, which also overexpress its receptors (IL-4R) ^[17][55].

Interleukin-5 (IL-5) is mainly produced by T helper-2 (Th2) lymphocytes and group 2 innate lymphoid cells (ILC2). It can increase antibody secretion by promoting the differentiation and growth of B cells and enhance the humoral immune response mediated by Th2 cells. Immunity to tumors is mainly controlled by Th1-mediated cellular immunity. If Th1-Th2 drift occurs, it will lead to an immunosuppressive response and the development of cancer ^[18][56]. IL-5 is involved in a number of immune responses, such as helminth infection and allergies. It also plays an important role in innate immunity by maintaining B-1 B cells and mucosal IgA production ^[19][57].

Interleukin-6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development to wound healing, ageing, inflammation, and immunity, including immunity to COVID-19 ^[20][58]. When homeostasis is disrupted by infections or tissue injuries, IL-6 is produced immediately and contributes to host defense against such emergent stress through the activation of acute-phase and immune responses. However, dysregulated excessive and persistent synthesis of IL-6 has a pathological effect on acute systemic inflammatory response syndrome and chronic immune-mediated diseases ^[21][59].

Interleukin-7 (IL-7) is a multipotent cytokine that maintains the homeostasis of the immune system. It plays a vital role in T-cell development, proliferation, and differentiation, as well as in B-cell maturation through the activation of the IL-7 receptor (IL-7R) ^[22][60]. IL-7 presents antitumor effects in tumors such as glioma, melanoma, lymphoma, leukemia, prostate cancer, and glioblastoma. In vivo administration of IL-7 results in a decreased cancer cell growth in murine models. IL-7 can also induce the production of IL-1α, IL-1β, and TNF-α by monocytes and can also help to inhibit melanoma growth ^[23][61].

Interleukin-8 (IL-8), alternatively known as CXCL8, is a pro-inflammatory CXC chemokine. CXCL-8 is a chemoattractant factor for myeloid leukocytes that is produced in large quantities by many solid tumors. Levels of IL-8, which can act upon a variety of immune and nonimmune cells, can provide significant information about tumors, including their size and how likely they are to respond to immunotherapy. This is because the IL-8 produced by tumors can promote angiogenesis, recruit immunosuppressive cells like neutrophils and myeloid-derived suppressor cells (MDSCs), and stimulate epithelial-to-mesenchymal transitions, which is a precursor to metastasis ^[24][62]. CXCL8 is one of the dominant transcriptional targets of the inflammatory signaling mediated by nuclear factor-κB (NF-κB), which is commonly activated in cancer cells. CXCL8 is a pro-inflammatory chemokine that acts on leukocytes and endothelial cells via their CXCR1 and CXCR2 receptors to promote immune infiltration and angiogenesis, which in turn establishes a venue for cancer cell local invasion, migration, and metastasis. As an angiogenic chemokine, CXCL8 binds with high affinity to both the CXCR1 and CXCR2 receptors, contributing to its function in the cancer microenvironment ^[25][63].

Interleukin-10 (IL-10) is a pleiotropic cytokine that plays a fundamental role in modulating inflammation and maintaining cell homeostasis. It primarily acts as an anti-inflammatory cytokine by protecting the body from an uncontrolled immune response, mostly through the Jak1/Tyk2 and STAT3 signaling pathways. On the other hand, IL-10 can also have an immunostimulating function under certain conditions ^[26][64]. IL-10 inhibits the secretion of cytokines, such as IL-1, IL-6, IL-12, IL-18, IL-23, and tumor necrosis factor (TNF), and promotes the differentiation of naïve CD4+ T cells into Tregs. It has been shown that IL-10 has a pivotal role in limiting an excessive inflammatory response, thus reducing collateral host damage while clearance of the pathogen is under way. IL-10 also has a beneficial role in limiting autoimmune diseases ^[27][65].

Interleukin-12 (IL-12) is a potent, pro-inflammatory type 1 cytokine that has long been studied as a potential immunotherapy for cancer ^[28][66]. It is involved in both the innate and adaptive immunity that stimulate T and natural killer cell activity and induce interferon gamma production. IL-12 has been identified as a potential immunotherapeutic component for combinatorial cancer treatments ^[29][67]. IL-12 can be considered a strong candidate for immunotherapy-based interventions, as it potentiates tumor-specific cytotoxic NK and CD8+ T cells that are largely responsible for tumor cell killing. However, the systemic administration of IL-12 is quite toxic; therefore, alternative methods of IL-12 delivery and/or the activation of T cells by IL-12 are needed ^[30][68].

Interleukin-15 (IL-15) is a cytokine that belongs to the interleukin-2 (IL-2) family and is essential for the development, proliferation, and activation of immune cells, including natural killer (NK) cells, T cells, and B cells ^[31][69]. In addition to using IL-15 and its derivatives alone in cancer immunotherapy, IL-15 has also been incorporated into many adoptive cell therapies against cancer, specifically in combination with chimeric antigen receptor (CAR) engineering. In many recent studies, researchers have attempted to incorporate IL-15 not only in ex vivo precultures but also by integrating IL-15 and its receptor in CAR engineering ^[32][70].

Interleukin-18 (IL-18) is an immunostimulatory cytokine belonging to the IL-1 family. It can regulate both innate and adaptive immune responses through its effects on natural killer (NK) cells, monocytes, dendritic cells, T cells, and B cells. It can equally act synergistically with other pro-inflammatory cytokines to promote interferon-γ (IFN-γ) production by NK cells, T cells, and possibly other cell types. Systemic administration of IL-18 has been shown to result in significant antitumor activity in several preclinical animal models ^[33][71].

Interleukin (IL)-21 is a cytokine produced by activated conventional CD4+ T lymphocytes and natural killer T cells, driving anti-tumor immunity in the skin and kidney. It can equally be identified as pro-inflammatory in many tissues, and it promotes colitis-associated colon cancer ^[34][72]. Initially, IL-21 was recognized for its anti-tumor effects in several preclinical tumor models, warranting its currently ongoing clinical development as a cancer immunotherapeutic. More recently, IL-21 has been associated with the development of a panel of autoimmune and inflammatory diseases, and neutralization of IL-21 has been suggested as a potential new therapy ^[35][73].

Interleukin-23 (IL-23) has been recently identified as a heterodimer cytokine with components related to the IL-6 family of cytokines ^[36][74]. IL-23 promotes the differentiation of Th17 cells, which orchestrates neutrophil-initiated resistance to extracellular bacteria and inflammation ^[37][75].

Granulocyte macrophage colony-stimulating factor (GM-CSF) is a cytokine that drives the generation of myeloid cell subsets including neutrophils, monocytes, macrophages, and dendritic cells in response to stress, infections, and cancers ^[38][76]. GM-CSF was identified as a hematopoietic growth factor that causes granulocyte and macrophage colony formation. It is used for DC generation from bone marrow cells or monocytes in vitro. At steady state, however, GM-CSF-deficient mice exhibit no defects in the development of myeloid cells, with the exception of alveolar macrophages and specific DC subsets in nonlymphoid tissues. Instead, GM-CSF plays a role in tissue inflammation and autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, asthma, psoriasis, and type I diabetes ^[39][77].

Interferon-α (INF-α) has a number of biological effects, including the inhibition of tumor cell growth through mechanisms that are not well understood. The role of INF-α in the treatment of non-Hodgkin’s lymphomas (NHL) was first investigated in a preclinical model of the AKR/J mouse ^[40][78]. Phase II trials involving IFN-α were conducted by the National Cancer Institute in non-Hodgkin lymphoma (NHL) patients. Conflicting results were seen with regards to the impact of IFN-α induction monotherapy and maintenance, and when combined with chemotherapy, on the survival of NHL patients. IFN-α was used in treating low-grade indolent NHLs, where it showed some activity; however, the complete response (CR) and overall response rates were only 10% and 48%, respectively ^[41][79].

Interferon-γ (IFN-γ) plays a key role in the activation of cellular immunity, and subsequently, the stimulation of the antitumor immune response. Based on its cytostatic, pro-apoptotic, and antiproliferative functions, IFN-γ is considered potentially useful for adjuvant immunotherapy for different types of cancers. Moreover, IFN-γ may inhibit angiogenesis in tumor tissue, induce regulatory T-cell apoptosis, and/or stimulate the activity of M1 proinflammatory macrophages to overcome tumor progression ^[42][80].

The transforming growth factor beta (TGF-β) cytokine has a research history of more than 40 years. TGF-β is secreted by many tumor cells and is associated with tumor growth and cancer immunity. The canonical TGF-β signaling pathway, SMAD, controls both tumor metastasis and immune regulation, thereby regulating cancer immunity. TGF-β regulates multiple types of immune cells in the tumor microenvironment, including T cells, natural killer (NK) cells, and macrophages. One of the main roles of TGF-β in the tumor microenvironment is the generation of regulatory T cells, which contribute to the suppression of anti-tumor immunity ^[43][81]. TGF-β is necessary for lung organogenesis and homeostasis, as evidenced by genetically engineered mouse models. TGF-β is crucial for epithelial–mesenchymal interactions during lung branching morphogenesis and alveolarization. Expression and activation of the three TGF-β ligand isoforms in the lungs are temporally and spatially regulated by multiple mechanisms ^[44][82].