Unlocking the Perplexity of Type I Interferons and STAT2 Signaling: A Comprehensive Review on its Implications in Cancer Biology and Immunotherapy

The tumor microenvironment refers to the cellular and non-cellular components that surround a tumor. It includes various cell types, including immune cells, fibroblasts, and blood vessels, as well as signaling molecules and extracellular matrix proteins. The tumor microenvironment plays a crucial role in tumor growth, progression, and response to therapy. It can promote or inhibit tumor development through interactions between tumor cells and the surrounding stromal cells, immune cells, and other components. It is important to understand the tumor microenvironment for the development of effective cancer treatments. One intriguing player in this intricate cellular network is the transcription factor STAT2, which is a downstream effector of the type I interferon (IFN-I) signaling pathway. The IFN-I family of cytokines is well-documented for its antiviral, antitumor, and immunomodulatory activities. Accumulating evidence suggests that STAT2 can exhibit both inhibitory and promotive effects on tumorigenesis depending on the specific context of each cancer type.  A new paper published in the peer-reviewed Journal Cytokine by Jorge Canar, Kennedy Darling, Ryan Dadey, and Professor Ana Gamero from the Lewis Katz School of Medicine at Temple University explores the diverse roles of STAT2 in shaping the tumor microenvironment, its involvement in antitumor immunity, and its potential impact on chemoresistance.  The paper provides a comprehensive analysis and current state of the field which offers a valuable resource for scientists and clinicians, who want to understand the potential of IFN-I signaling in cancer immunotherapy and personalized medicine.

The research team discusses in depth IFN-I signaling pathways. Upon binding to the IFN-I receptor, IFN-I initiates signaling cascades that involve the phosphorylation, dimerization, and nuclear translocation of STAT1 and STAT2. Together with interferon regulatory factor 9 (IRF9), these proteins form the IFN stimulated gene factor 3 (ISGF3) complex, which regulates the expression of IFN-stimulated genes (ISGs).  The canonical view suggests that IFN-I/ISGF3 signaling induces the expression of genes with antitumor properties. However, recent studies highlight a non-canonical pathway in which STAT2/IRF9 heterodimers, in the absence of STAT1, can drive IFN-I transcriptional responses. Additionally, unphosphorylated ISGF3 (U-ISGF3) can mediate late IFN-I responses. The dualistic nature of IFN-I signaling via STAT2 raises intriguing questions about its impact on tumorigenesis and the tumor microenvironment.

IFN-I has various clinical uses due to its immunomodulatory and antiviral properties. It is commonly used in the treatment of certain viral infections, such as hepatitis B and C, and human papillomavirus (HPV). IFN-I is also employed in the management of certain autoimmune diseases, such as multiple sclerosis. Additionally, it has been investigated for its potential use in cancer immunotherapy. However, its widespread use is limited due to severe adverse reactions. New preclinical studies using animal models have shown the importance of endogenous IFN-I in tumor immunosurveillance, anti-angiogenesis, and metastasis control. The timing, dosage, and frequency of IFN-I administration are crucial factors that determine its efficacy in suppressing metastasis. Recent research has also focused on the presence of an IFN-I transcriptional signature in the tumor microenvironment as a favorable prognostic marker for therapeutic response. Tumors with impaired IFN-I signaling, known as “cold tumors,” are associated with poor prognosis and resistance to immune checkpoint inhibitors. The development of next-generation IFN-I therapies with improved efficacy and reduced toxicity is an ongoing area of investigation.

It is well-known that the invasive behavior of cancer cells is influenced by the tumor microenvironment. The authors discussed the studies that showed that higher levels of STAT1 and STAT2 are associated with the induction of an amoeboid phenotype in melanoma cells, which enhances their invasive capabilities. The IFN-I/ISGF3 pathway plays a critical role in promoting cancer invasion plasticity. Understanding the crosstalk between different invasion strategies, such as the epithelial-mesenchymal transition and amoeboid modes, is crucial for unraveling the mechanisms underlying tumor cell motility and invasion.

The interaction between tumor cells and immune cells in the tumor microenvironment is a key determinant of cancer progression. IFN-I signaling through STAT2 can modulate the immune response in a context-dependent manner. In some cancers, IFN-I can stimulate the production of chemokines that attract immune cells to the tumor site, enhancing antitumor immunity. Conversely, in certain contexts, IFN-I signaling can induce immune suppressive factors and promote the recruitment of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells. The balance between pro- and anti-tumor immune responses mediated by STAT2/IFN-I signaling is complex and requires further investigation.

Chemoresistance remains a significant challenge in cancer treatment. Emerging evidence suggests that STAT2 may play a role in mediating resistance to chemotherapy agents. In some cancer types, elevated STAT2 expression has been associated with resistance to chemotherapy-induced cell death. The underlying mechanisms by which STAT2 contributes to chemoresistance are not yet fully understood and require further exploration. Understanding the interplay between STAT2 and chemotherapy response could lead to the development of novel strategies to overcome drug resistance.

In conclusion, Temple University scientists led by Professor Ana Gamero showcased their expertise in deciphering the intricate mechanisms underlying IFN-I signaling in cancer. The role of STAT2 in cancer is also multifaceted, with both pro- and anti-tumorigenic effects depending on the specific cellular environment. Its involvement in IFN-I signaling pathways adds complexity to the understanding of tumor immunology and therapeutic strategies. According to the authors, further research is needed to unravel the intricate interactions between STAT2, IFN-I, and the tumor microenvironment, which may pave the way for the development of targeted therapies that harness the potential of STAT2 signaling in cancer treatment.