Abstract
Type I interferons (IFNs), particularly IFNα and IFNβ, have an important role in cancer therapy, enhancing antitumour immunity and improving the efficacy of both conventional treatments and immunotherapies. However, despite considerable investment and research in IFN-based treatments, clinical success in solid malignancies has been hampered by toxicity and limited therapeutic efficacy. Recent studies show that type I IFNs can exert both immune-stimulatory and immune-suppressive effects within tumours, with their activity shaped by oncogenic signalling, chromatin state, the tumour microenvironment and therapeutic interventions. In this Review, we explore current insights into the regulation and function of type I IFNs in cancer, with a particular focus on tumour-intrinsic mechanisms controlling canonical and chronic signalling. We examine how these pathways influence immune surveillance, metastatic progression, therapeutic response and resistance. We also discuss how age-related changes, including immunosenescence and alterations in stromal composition and function, modulate type I IFN signalling and affect therapeutic outcomes. By dissecting the transcriptional, epigenetic and signalling mechanisms that control type I IFN responses, we outline actionable strategies to reprogramme IFN activity in tumours and ultimately improve response to therapies.
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Acknowledgements
This work was supported by National Health and Medical Research Council (NHMRC) investigator, and ideas grant to B.S.P. (2018167, 2012943), and grant funding from the National Breast Cancer Foundation (IIRS-23-021) and Cancer Council Victoria (GIA2024).
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B.S.P. is chief scientific officer and a shareholder of AlleSense (Australia). This entity had no influence on this publication. All other authors declare no competing interests.
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Glossary
- Abscopal response
-
A systemic, immune-mediated antitumour effect of localized radiation therapy, whereby regression of tumours outside the irradiated field occurs following irradiation of a primary or distal site.
- Adenosine
-
A naturally occurring compound that functions as a key metabolite in energy transfer and as an extracellular signalling molecule that regulates diverse physiological and immune processes.
- Aicardi–Goutières syndrome
-
A rare, inherited genetic disorder characterized by chronic overproduction of type I interferons, leading to early-onset neurological abnormalities, immune dysregulation and systemic inflammation that mimic congenital viral infection.
- Armoured CAR T cells
-
Chimeric antigen receptor (CAR) T cells that are further modified to express additional factors, such as cytokines, checkpoint inhibitors or dominant negative receptors, to enhance their persistence, overcome immunosuppression and improve antitumour efficacy within hostile tumour microenvironments.
- Chromatin
-
A complex of DNA and associated proteins found in eukaryotic cells. The core proteins, mainly histones, package and organize DNA into a compact structure, allowing it to fit within the nucleus while regulating expression and genome stability.
- Chromosomal segregation
-
The process during cell division by which duplicated chromosomes are separated and distributed into daughter cells, ensuring each cell inherits the correct genetic material.
- Dormancy
-
A reversible state of growth arrest and reduced metabolic activity that allows tumour cells to evade immunity and therapy, yet retain the potential to reactivate and cause recurrence.
- Endogenous retroviral elements
-
(ERVs). Ancient retroviral sequences in germline DNA that, when transcriptionally reactivated, can influence gene regulation, immune signalling and cancer.
- Epigenetic
-
Relating to changes, including heritable changes, in gene expression that occur without altering the underlying DNA sequence, typically through mechanisms such as DNA methylation, histone modification and chromatin remodelling.
- Genomic instability
-
An increased tendency of cells to acquire genetic alterations, including mutations, chromosomal rearrangements, copy number variations and aneuploidy, typically arising during cell division or in response to DNA damage.
- Helicases
-
An enzyme that unwinds and remodels nucleic acid structures, such as DNA or RNA duplexes, often using energy from ATP hydrolysis, to facilitate processes such as replication, transcription, repair and RNA metabolism.
- Immunogenicity
-
The ability of a substance, such as a pathogen, tumour cell or therapeutic agent, to elicit an immune response, including activation of innate and adaptive immune cells.
- Inflammatory memory
-
A long-lasting transcriptional or epigenetic reprogramming of innate immune or epithelial cells after prior inflammatory or environmental stimuli, enabling altered or heightened responses to subsequent stimuli.
- Long interspersed nuclear elements
-
(LINEs). A group of non-long terminal repeat (LTR) retrotransposons (also called class I transposable elements) found throughout the eukaryotic genomes that propagate by transcription into RNA and are subsequently reverse-transcribed to enable insertion into new genomic locations.
- Menopause
-
The natural and permanent cessation of menstrual periods in women, resulting from the decline of ovarian follicular activity and decreased production of oestrogen and progesterone.
- Micrometastasis
-
Very small clusters of cancer cells ranging from 0.2 mm to 2 mm in size that have disseminated from a primary tumour to distal sites but are too small to be detected using standard imaging and diagnostic tests.
- Micronuclei
-
Small, extranuclear bodies that form when whole chromosomes or chromosome fragments fail to be incorporated into daughter nuclei during cell division, often serving as a marker of genomic instability and DNA damage.
- Monogenic interferonopathies
-
A group of rare genetic disorders caused by single-gene mutations that lead to constitutive or dysregulated type I interferon signalling, resulting in autoinflammation, tissue damage and clinical features resembling viral infection.
- Oestrogen
-
A steroid hormone that has a key role in the development and regulation of the female reproductive system and secondary sexual characteristics, and also influences bone health, cardiovascular function and immune responses.
- Plasmacytoid dendritic cells
-
(pDCs). Specialized dendritic cells that produce large amounts of type I interferons in response to viral infections and other nucleic acid stimuli, linking innate and adaptive immunity by sensing pathogens through Toll-like receptors and promoting T cell activation.
- Progesterone
-
A steroid hormone that regulates the menstrual cycle, supports pregnancy and modulates immune and reproductive tissue function.
- Quiescence
-
A reversible, non-dividing cellular state characterized by reduced metabolic activity, allowing cells to conserve energy and survive under unfavourable conditions while retaining the capacity to re-enter the cell cycle.
- R-loops
-
Three stranded nucleic acid structures that form when RNA binds to its complementary DNA strand, displacing the non-template strand, altering transcription and, if persistent, compromising genomic stability.
- Retroelements
-
Mobile genetic elements that can move through the genome via an RNA intermediate, which is reverse-transcribed into DNA and inserted at a new genomic location.
- Senescence
-
A stable, non-dividing cellular state in which cells remain metabolically active and often secrete inflammatory factors.
- Short interspersed nuclear elements
-
(SINEs). Non-autonomous retrotransposons, typically 100–400 bp long, that are found in eukaryotic genomes; they are transcribed into RNA and are subsequently reverse-transcribed by enzymes encoded by other retroelements to facilitate their insertion into new genomic locations.
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Chadwick, T.B., So, J., Hertzog, P.J. et al. Striking the right balance with type I interferon signalling in cancer. Nat Rev Cancer (2026). https://doi.org/10.1038/s41568-026-00915-1
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DOI: https://doi.org/10.1038/s41568-026-00915-1
