Over time, the global rise in cancer incidence and mortality has corresponded with an increase in a range of cancer-related lifestyle factors, such as obesity and inactivity (Bray et al., 2018); thus, optimizing lifestyles and exercise (Anand et al., 2008) have been emphasized as tools for cancer prevention and management (Bourke et al., 2016; Gunnell et al., 2017). Exercise oncology-the application of sports medicine to cancer is a rapidly growing subspecialty within the field of clinical oncology, and the quantity and quality of research in this area are increasing (Jones and Alfano, 2013). Although substantial evidence has supported a link between exercise and reduced progression and mortality in several types of cancer: Exercise-induced myokines play an important role in increasing cytotoxicity and the infiltration of immune cells into the tumour on prostate cancer. Myokines released from activated skeletal muscle impaired growth and migration of PC(Pancreatic cancer) cells and enhanced PC cell death. However, the molecular mechanism between exercise and disease progression has not been fully elucidated. (Kim et al., 2021; Schwappacher et al., 2021). Research suggests that exercise could lead to a variety of physiological alterations, thereby reducing the risk of developing chronic disease. For example, the factors such as muscle secretome and catecholamines in serum will be regulated after exercise. (Jones and Alfano, 2013; Rönn et al., 2014; Bohlen et al., 2018; Chen et al., 2022). Preclinical evidence suggested that exercise may modulate levels of systemic factors such as local growth factors (IGF1), hormones (insulin and leptin), and inflammatory cytokines (IL-6, IL-15), which are known factors that have a possible impact on the cancer process (Kim et al., 2021). It has been determined that skeletal muscle is a significant source of IL-15 (rEF.146). After a single exercise session, IL-15 mRNA expression in skeletal muscle (Bohlen et al., 2018; Kim et al., 2021; Morrisson et al., 2021) was much greater in healthy volunteers than it was before the exercise (Riechman et al., 2004; Tamura et al., 2011). It was also widely reported that circulating levels of IL-15 were significantly higher after many kinds of exercise, which may benefit human health (Riechman et al., 2004; Nielsen et al., 2007; Tamura et al., 2011; Jones and Alfano, 2013; Bazgir et al., 2015; Crane et al., 2015; Palareti et al., 2016).

Interleukin 15 (IL-15) is a cytokine of the interleukin 2 (IL-2) family that has multiple functions similar to IL-2 in regulating the adaptive and innate immune systems (Bohlen et al., 2018). Although IL-15 is released in small amounts, the alpha receptor (IL15Rα), a transmembrane protein with a high affinity for IL-15, facilitates IL-15 transport from the endoplasmic reticulum through the cytoplasm and presents the IL-15/IL-15Rα complex on the cell surface (Nadeau and Aguer, 2019). Upon cell activation, IL-15 is secreted primarily by dendritic cells (DCs), macrophages, and monocytes (Do Thi et al., 2019); however, it can also be secreted by many other cell types, including endothelial cells, mesenchymal cells, and renal epithelial cells, but not by T cells or natural killer (NK) cells (Nielsen et al., 2007; Vilsmaier et al., 2021). With improved immune cell activation and migration, IL-15 is involved in anti-tumor immunity (Morrisson et al., 2021; Schwappacher et al., 2021; Vilsmaier et al., 2021). Many studies suggested that IL-15 is involved in tumor suppression by enhancing anti-tumor immunity (Crane et al., 2015; Dethlefsen et al., 2017; Bohlen et al., 2018; Liu et al., 2021). In recent years, many studies have been conducted to investigate the oncogenesis and development of pan-cancer to reveal the similarities and differences in cancer (Xu et al., 2021; Zhang et al., 2022). Therefore, it is of interest to further explore the spectrum of oncogenes in pan-cancer, but to date, there is no association analysis between IL-15 and pan-cancer.

Ferroptosis and cuproptosis are two forms of cell death induced by unbalanced ion homeostasis, which ferroptosis is driven by iron-dependent lipid peroxidation, while cuproptosis terms to intracellular copper accumulation triggers the aggregation and destabilization of proteins (Stockwell, 2022; Tang et al., 2022). A better understanding of the molecular determinants of the two cell death modes will contribute to innovate anticancer therapies (Lei et al., 2022; Tsvetkov et al., 2022). For example, much research has revealed that drugs targeting ferroptosis could kill cancer cells both in vitro and in vivo (Lei et al., 2022). Studies have reported CD8⁺ T cells could activate ferroptosis in tumor cells in vivo and further induce cancer cells death(32778143). But currently, rare studies have discovered the association between IL-15 and ferroptosis/cuproptosis-related genes in pan-cancers, which is wealthy to explore.

We have systematically investigated the role of IL-15 in human pan-cancer. We comprehensively investigated the different expression levels of IL-15 in tumor and normal control tissues by using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEX), and tumor-related databases. The predictive value of IL-15 on prognosis was also evaluated. Meanwhile, potential relationships between IL-15 mRNA expression levels and clinical features, DNA gene mutations, immune cells infiltration, and pathway regulation were evaluated in pan-cancer. This study highlights the multifaceted role of IL-15 in pan-cancer. Combined with its correlation with exercise, we provide a theoretical basis for exercise to prevent cancer and IL-15 as a pan-cancer therapeutic target.

Numerous studies have shown that circulating levels of IL-15 are elevated in humans for 10–120 min following an acute exercise (Riechman et al., 2004; Tamura et al., 2011; Crane et al., 2015). For example, Regular endurance training for 12 weeks led to a 40% rise in the amount of IL-15 protein in the basal skeletal muscle (Rinnov et al., 2014). Weightlifting increased circulating IL-15 levels in untrained and trained young subjects during and immediately after exercise (Nielsen et al., 2007; Bazgir et al., 2015; Nadeau and Aguer, 2019; Kim et al., 2021). Recently, IL-15 has emerged as a promising cytokine for the treatment of cancer (Berger et al., 2019; Ligibel et al., 2019; Xiao et al., 2019; Schwappacher et al., 2021; Pereira et al., 2022). IL-15 is also a key factor in the development, proliferation, and activation of NK cells and CD8⁺ T cells (Berger et al., 2019; Do Thi et al., 2019; Fiore et al., 2020; Liu et al., 2021), which are able to destroy cancer cells in the tumor microenvironment. Several current products include ALT-803 ALT-803 (Hu et al., 2018), P22339 (Hu et al., 2018), chimeric IL-15 apolipoprotein A-I (Ochoa et al., 2018), or NKTR-255 (Miyazaki et al., 2021), illustrating the promise of IL-15 in cancer therapy. Recently, some completed clinical trials have reported usage of recombinant human single-chain IL-15 and IL-15 superagonist in cancer treatment (Zhang et al., 2021). Conlon et al. utilized recombinant human single-chain IL-15 to treat metastatic malignant melanoma or renal cell cancer patient with maximum tolerated dose 0.3 ug/kg (Conlon et al., 2015). The results indicated IL-15 could dramatically mediate the NK cells in blood. In the following study by Conlon et al.and Miller et al., the results showed a better mediated effect to NK cells and CD8⁺ cells when the maximum tolerated dose up to 2 ug/kg (Miller et al., 2018; Conlon et al., 2019). However, no studies have explored IL-15 in pan-cancer, limiting its possible clinical application, and the present study has explored the relevance by focusing on both prognostic and immunological directions.

It was found in this study that IL-15 is highly expressed in the thyroid, intestine, bone marrow, and lymphatic system, while it is less expressed in tissues such as skin and pancreas and varies independently of sex. It was also decreased in most tumor cell lines and was highly expressed in epithelial cells and monocytes, which are similar to the previous reports (Van Acker et al., 2018; Nadeau and Aguer, 2019; Xiao et al., 2019; Liu et al., 2021). IL-15 gene expression was found to be downregulated in BLCA, BRCA, COAD, LUAD, PRAD, READ, THCA, and UCEC in both matched and unmatched specimens in the TCGA database, GTex database, and TIMER database. We further examined IL-15 expression in tissues and found that the relative expression of IL-15 protein was downregulated in COADREAD, LUAD, BRCA, and BLCA. Currently, rare studies have checked the IL-15 expression in pan-cancer using tissue microassays except in those databases. Cierna et al. (2021) found that decreased levels of circulating IL-15 suggested PD-L1 overexpression in tumors of primary breast cancer patients and poor prognosis. Krizia et al. (Cierna et al., 2021) reported that higher IL-15 levels would lead to better outcomes in prostate cancer, which is consistent with our findings. Margolin et al. (2018) recently found that the injection of IL-15N72D: IL-15RαSu/IgG1 Fc complex could reduce cancer growth, induce NK cell expansion and improve survival in patients with incurable advanced melanoma, renal cell, non-small cell lung, and head and neck cancer. The above results suggest that IL-15 plays an important role in the development of human cancers.

Next, we sought to analyze the relationship between mRNA expression levels of IL-15 and the prognosis of patients with cancer. Kaplan-Meier survival analysis showed that OS in LUAD, COAD, COADREAD, SKCM, UCS, and READ, OS in LUAD, COAD, COADREAD, SKCM, UCS and READ, PFI in ESCA, COADREAD, COAD, LUAD, READ, and DSS in SKCM were positively correlated with IL-15 expression, with statistically significant differences. In addition, we found that IL-15 was significantly lower in COAD, SKCM, and COADREAD with worse clinical staging compared to patients with lower staging. These results may confirm that IL-15 plays a protective role in human cancers. However, we also found that mRNA expression levels of IL-15 played a cancer-promoting role in GBM, OSCC, LGG, THYM, LIHC, LAML, PAAD, and GBMLGG. These suggest that the mechanism of IL-15 in cancers are complex and IL-15 may play a negative role in certain cancer types in a specific condition, which will need to be further tested in the future (Waldmann, 2014; Fiore et al., 2020; Cierna et al., 2021). For example, overexpression of IL-15 mRNA is associated with clinical staging and metastasis in cutaneous T-cell lymphoma (Döbbeling et al., 1998), but we found from the Kaplan-Meier database that IL-15 is more likely to be a protective factor for patients with SKCM. In addition, clinical studies have reported a correlation between high intra-tumor IL-15 concentrations and poor clinical outcomes in patients with lung cancer (Seike et al., 2007), which is contrary to our results. We suspect that the discrepancy between our online database results and the reported data may be due to the different methods used to detect IL-15 expression. Gene expression of IL-15 in lung adenocarcinoma, whereas mRNA and protein expression of IL-15 was detected in the Kaplan-Meier and Atlas databases. Therefore, the result of this study should be further validated in corresponding cancer samples for deeper investigation.

The IL-15 gene is located on chromosome 4q31 and encoded the 14–15 kDa glycoprotein-IL-15(54). IL-15 deficiency, due to mutations in its gene, has been extensively studied in many diseases, such as liver injury (Hou et al., 2012), diabetes (Liu et al., 2017) and allergy (Mathias et al., 2017). However, there are rare studies on the alteration of the IL-15 gene in human tumors. Therefore, we used the cBio-portal database to reveal the fact that amplification is the greatest frequency of IL-15 changes in pan-cancer. Alterations in IGLVIL-66-1, ALC5A6, Lnc00189, MFSD13B, PPP1R1A, REX1BD, NUP50-DT, and SKP1P2 were found to co-exist among IL-15 mutations. However, by our assay, we found that IL-15 variants do not seem to affect the prognosis of cancer patients (data not presented). Furthermore, studies have reported that if IL-15 deficiency leads to a range of problems (Gillgrass et al., 2014; Mathias et al., 2017; Van Acker et al., 2018; Schwappacher et al., 2021), suggesting that these variants may not affect the functional profile of IL-15 in cancer.

Due to a marked reduction in the number of peripheral lymphocytes, NK cells, T cells in IL-15-deficient mice (Grabstein et al., 1994; Miller et al., 2018), we believed that IL-15 may play an important role in the immune regulation of human tumors. Firstly, we used the ssGSEA algorithm in the TCGA database and found that IL-15 was positively associated with a range of immune cells including aDC, B cells, CD8⁺ T cells, Cytotoxic cells, DC, Eosinophils, iDC, Macrophages, Neutrophils, NK CD56^- cells, NK cells, T cells, T helper cells, Tcm, Tem, fh, Tgd, Th1 cells, and Treg. Only NK CD56⁺ cells, Th2 cells, Mast cells, and pDC were not significantly positively correlated with IL-15 expression. Timer database mining further revealed that IL-15 expression was significantly correlated with infiltration levels of a variety of immune-related cells, including B cells, CD8⁺T cells, CD4⁺T cells, neutrophils, macrophages, and dendritic cells in LUAD, COAD, SKCM, ESCA, and USC. The role of IL-15 in the human immune system has been studied in recent years. In mouse models, exogenous IL-1t5 treatment can reverse the downregulation of NK cell and T cell activity in IL-15 deficient mice (Kennedy et al., 2000). In terms of the cancer microenvironment, systemic IL-15 treatment reduced tumor growth, metastasis, and recurrence by increasing the cytotoxic effects of NK cells in mice inoculated with a lung and breast cancer models (Tang et al., 2008; Gillgrass et al., 2014). A preclinical study showed reduced tumor growth and increased immune cell infiltration in a mouse model of prostate cancer with IL-15 overexpression 2.5-fold and 2.7-fold higher numbers of CD8⁺ T cells and NK cells, respectively than in mice in the model without IL-15 injection (Morris et al., 2014). Our study suggested that IL-15 could also be useful in LUAD, COAD, SKCM, ESCA, and USC by improving the infiltration of the immune cells in tumors.

Furthermore, it has been suggested that IL-15 plays an important role in modulating lipid metabolism and glucose metabolism (Nadeau and Aguer, 2019; Kim et al., 2021). In mice, high levels of circulating IL-15 prevented abnormal glucose tolerance and insulin resistance induced by the high-fat diet. Overexpression of muscle-specific IL-15 in mice and supraphysiological IL-15 treatment in rats resulted in lower respiratory exchange rates and higher whole-body fatty acid oxidation, showing a greater tendency to use lipids as a high-energy fuel (Almendro et al., 2006; Morris et al., 2014). The series of abnormal expressions of lipid metabolism and gluconeogenic signaling pathways that may be induced by the reduction of IL-15 in pan-cancer may lead to the metabolic dysfunction of the body in the development of cancer (Crane et al., 2015; Bohlen et al., 2018; Nadeau and Aguer, 2019). This can at least partly explain why the upregulated IL-15 gene expression can be a risk factor in OS of GBM, OSCC, LGG, THYM, LIHC, LAML, PAAD, and GBMLGG in our results. Moreover, GPCR ligand binding, infection, phagocytosis, and DNA damage checkpoints were found to be IL-15 mediated pathways in pan-cancer, which deserved further investigation.

Finally, we analyzed the relationship between IL-15 and ion-induced death and their impact on clinical prognosis. Our results show that IL-15 is positively associated with ferroptosis/cuproptosis-related genes in various types of tumors, such as LIPT1, ACSL4. High expression of these genes can improve the prognosis of patients with SKCM and LUAD, which suggests that IL-15 may be able to kill cancer cells by activating the process of ferroptosis/cuproptosis. The literature reports that loss ACSL4 will promote cancer progress and enhanced ACSL4 expression will result in better clinical outcomes in tumors (Liao et al., 2022). Furthermore, high LIPT1 expression was reported to be a good prognostic factor in SKCM (Lv et al., 2022), which is in line with our work. IL-15 may be in synergy with ferroptosis/cuproptosis inducers for tumor treatment in the future.

Further studies can continue to delve into the evidence of potential associations between IL-15 expression and DNA mismatch repair system, microsatellite instability, ferroptosis/cuproptosis, or tumor mutation burden, and explore the possibility that IL-15 may influence the response of cancer patients to immune checkpoint therapy, which will contribute to further understanding of the mechanisms of immunotherapy for cancer treatment. In addition, pharmacological target exploration can be performed to search for drugs that can target or synergize IL-15 and contribute to clinical cancer treatment.

This study systematically evaluated the characteristics of IL-15 in various aspects, including expression pattern, survival prognosis, genetic mutation, tumor immune microenvironment, ferroptosis/cuproptosis, and signaling pathway. Exercise-induced IL-15 might serve as a potential candidate for multiple-cancer treatments since it showed low expression in multiple cancers and predicted a better prognosis in cancer patients. Moreover, the aberrant IL-15 expression may be related to the tumour immune microenvironment in multiple types of cancer. This study highlights the positive roles of IL-15 in pan-cancer and provides data-based insights for the application of IL-15 in cancer treatment.