Abstract
Tumor progression and transition into a metastatic state are largely dependent on the nature of the tumor microenvironment, which typically contains both tumor cells and other nontransformed cells. The dynamic interactions between these cells affect the progression of the tumor by either suppressing or promoting growth, migration, metastasis, and therapeutic resistance. Key regulators in this process are cytokines, small proteins up to 70 kDa, that instruct a variety of biological processes of cells.
Tumor cells and leukocytes in the tumor microenvironment are known to secrete cytokines that can both stimulate self-proliferation, expansion, and drug resistance in an autocrine manner, and induce recruitment, activation, and differentiation of other cells in the tumor microenvironment in a paracrine manner. Cytokines also commonly alert immune cells to the presence of infections and tissue damage. However, persistent cytokine production can lead to a chronic inflammatory state that promotes cancer growth.
Thus, cytokines in the tumor microenvironment may either establish an antitumor immune microenvironment or suppress antitumor immunity and exert direct tumor-promoting signals. Such yin-yang activity of tumor-induced cytokines depends on several tumor-specific variables, such as the tumor type, the stage of progression, the expression of certain receptors, and other microenvironmental components.
Inflammatory cytokines have long been proven to be an effective anticancer therapy. The vast pleiotropism and redundancy in cytokine signaling, as well as their dual immunosuppressive and immunostimulatory functions, coupled with safety requirements, are major challenges to their use in immunotherapies. However, they remain an important field of research. For example, interleukin (IL)-10 has been shown to exhibit anticancer effects by reducing tumor-promoting inflammation and stimulating CD8+ T cells in the tumor milieu (Carlini et al., 2023).
It also promotes inflammation through proinflammatory cytokine induction, such as interferon (IFN)-γ and granzyme B, which upregulate major histocompatibility complex class I/II expression for tumor antigen presentation. In its pegylated form, IL-10 effectively induces tumor rejection.
Although there is considerable optimism about the clinical application of cytokines to cancer immunotherapies, there remain significant challenges to enhancing their pharmacokinetics and pharmacodynamics, elucidating the role of genetic polymorphisms, and improving local administration. Clearly, there is a need to better understand the complex intricacies of tumor-induced inflammatory cytokines within the tumor microenvironment to harness them more effectively for anticancer therapies.
In addition to the therapeutic potential of cytokines against tumors, they may also serve as biomarkers to detect tumors, predict disease outcomes, and manage therapeutic choices. Newly formed blood and lymph vessels may facilitate the metastatic spread of cancer cells, and circulating cytokines could help establish and accelerate the metastatic capability of cancer cells. Moreover, the levels of circulating cytokines, such as IL-1α, IL-2, and IFN-α2, are useful for monitoring severe potentially life-threatening immune-related toxicity in response to checkpoint inhibitors (Lim et al., 2019).
Dysregulation in circulating cytokine levels has been correlated with the presence and severity of many types of cancers, as well as the effectiveness of certain therapies. Measurements of cancer-specific proteins and circulating cytokines from minimally invasive biopsies and blood samples may potentially serve as cancer diagnostics and perhaps determine tumor stages. For example, when combining IL-6, IL-8, and tumor necrosis factor measurements with cancer-specific proteins, such as carcinoembryonic antigen and cancer antigen-724, the screening power of gastric cancer was greatly improved (Li et al., 2018).
This approach to cancer detection is not only minimally invasive and cost-effective but also could be easily accessible as various analytical technologies are available without a requirement for exclusive instruments. In addition, peripheral immune cells from patients with certain types of cancer have dysregulated immune cytokine signaling signatures, which may add further information for diagnostics. For example, recent studies have identified dysregulated IL-6 secretion from peripheral blood T cells and dysregulated IFN-γ secretion from peripheral monocytes in cancer patients. This was also the case in patients who only had localized tumors. Therefore, there is considerable interest in using the cytokine signaling signatures of peripheral immune cells for cancer diagnosis and prognosis.
The measurement of multiple cytokines from a single sample might be necessary for accurate diagnosis and prognosis. Advances in molecular engineering, genomics, and molecular analysis hold promise to optimize the cytokine-based diagnostic and prognostic approaches in clinical settings for cancer. Interestingly, several new technologies have been developed to directly measure cytokine secretion from a single cell. Microfluidic devices capable of capturing specific single cells followed by the detection of multiple cytokines using specific antibodies and various biosensors have been developed. However, several requirements, especially standardization of sample handling and measurement procedures, must be addressed before these test methods can be effectively used in clinical settings.
The Journal of Interferon and Cytokine Research has commissioned a forthcoming special issue to report on the latest advances in understanding the different aspects, positive and negative, of tumor biology, diagnosis, and prognosis. The articles in this special issue will focus on all aspects of the roles of cytokines in the tumor microenvironment, in various stages of cancer development, and their potential use in diagnostic and prognostic approaches. Articles will also address development and application of highly generalizable and well-calibrated assays for measuring multiple cytokine levels in blood samples and tumor biopsies. The journal welcomes submission of original research reports, reviews, and perspectives related to, but not limited to: Cytokines in the tumor microenvironment The pro- and antiproliferative effects of cytokines on tumor growth Cytokine-induced post-transcriptional and post-translational processes Clinical translation of cytokine-based cancer immunotherapies Applications of circulating cytokine measurements Technological advances in inflammatory cytokine-based diagnosis and prognosis