Type I interferon and cancer

Abstract

SummaryType I interferon (IFN) is a class of proinflammatory cytokines with a dual role on malignant transformation, tumor progression, and response to therapy. On the one hand, robust, acute, and resolving type I IFN responses have been shown to mediate prominent anticancer effects, reflecting not only their direct cytostatic/cytotoxic activity on (at least some) malignant cells, but also their pronounced immunostimulatory functions. In line with this notion, type I IFN signaling has been implicated in the antineoplastic effects of various immunogenic therapeutics, including (but not limited to) immunogenic cell death (ICD)‐inducing agents and immune checkpoint inhibitors (ICIs). On the other hand, weak, indolent, and non‐resolving type I IFN responses have been demonstrated to support tumor progression and resistance to therapy, reflecting the ability of suboptimal type I IFN signaling to mediate cytoprotective activity, promote stemness, favor tolerance to chromosomal instability, and facilitate the establishment of an immunologically exhausted tumor microenvironment. Here, we review fundamental aspects of type I IFN signaling and their context‐dependent impact on malignant transformation, tumor progression, and response to therapy.

Mouse Type-I Interferon-Mannosylated Albumin Fusion Protein for the Treatment of Chronic Hepatitis

“…Type-I IFN exerts various biological activities, such as antiviral, antitumor, and immunomodulatory effects [ 10 ], which are its core medicinal properties, through the type-I IFN receptor. In particular, the anti-inflammatory effects of type-I IFN have recently attracted attention in clinical practice [ 56 ].…”

“…Since interferon (IFN) was discovered as a “virus suppressor” in 1953 [ 9 ], a variety of biological activities have been discovered, such as an anti-tumor effect [ 10 ], a proliferation-inhibiting effect [ 11 ], and a cell differentiation effect [ 12 ]. It has also recently been shown that type-I IFN (IFN-α and β) has the ability to induce IL-10 (an anti-inflammatory cytokine) [ 13 ], IL-1 receptor antagonist (IL-1Ra, an inflammasome inhibitor) [ 14 ], and programmed death-1 (PD-L1, an immune checkpoint molecule) [ 15 , 16 ] when it acts on the IFN receptors of macrophages.…”

Mechanisms of programmed cell death

“…In addition, cell death induction can result in the production of Type I interferons by tumor cells that then mediate ambiguous adaptive responses ranging from an enhancement of cancer cell stemness and exhaustion of anticancer immune response within the tumor microenvironment to the stimulation of anticancer immune responses. Type I interferon can even trigger a systemic sickness response ranging from flu‐like symptoms to a state of depression 2 . Such long‐range effects of cell death are certainly also relevant to the pathophysiology of viral infections.…”

“…Of note, there are multiple different subroutines of cell death, and several if not all of them can be immunogenic, as this has been documented for apoptosis (which involves mitochondrial membrane permeabilization and the activation of caspases 3 and 7) 2,3 but also for necroptosis (with the implication of specific effector molecules including receptor‐interacting kinase 3 (RIP3) and mixed lineage kinase domain‐like pseudokinase (MLKL1)), 6 pyroptosis (involving inflammasome/caspase‐1‐mediated activation of pore‐forming gasdermins), 7 a mixture of pyroptosis, apoptosis, and necroptosis dubbed PANoptosis, 8 ferroptosis (involving lethal membrane damage by peroxidation), 9,10 and cuproptosis (due to copper‐induced aggregation of lipoylated dihydrolipoamide S‐acetyltransferase) 11 . In all cases, cell death can be preceded by immunogenic stress that favors the emission of danger‐associated molecular patterns (DAMPs) appearing on the surface of the cells or secreted into the extracellular space.…”

Editorial: How to circumvent the tumour-promoting effect of cytokine in tumour therapy

“…Cytokines, a class of soluble proteins that are key mediators of cell communication in the tumour microenvironment (TME), can regulate both innate and adaptive immunity ( 1 , 2 ). Unfortunately, some tumour-related cytokines, especially pro-inflammatory cytokines (such as TNF, IL-6, and IL-1), have a well-recognized tumour-promoting activity and take part in the various phases of tumour initiation and progression ( 3 , 4 ).…”