Machete identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis
Open accessAbstract
The most prominent homozygous deletions in cancer affect chromosome 9p21.3 and eliminate CDKN2A/B tumor suppressors, disabling a cell-intrinsic barrier to tumorigenesis. Half of 9p21.3 deletions, however, also encompass a type I interferon (IFN) gene cluster; the consequences of this co-deletion remain unexplored. To functionally dissect 9p21.3 and other large genomic deletions, we developed a flexible deletion engineering strategy, MACHETE (molecular alteration of chromosomes with engineered tandem elements). Applying MACHETE to a syngeneic mouse model of pancreatic cancer, we found that co-deletion of the IFN cluster promoted immune evasion, metastasis and immunotherapy resistance. Mechanistically, IFN co-deletion disrupted type I IFN signaling in the tumor microenvironment, leading to marked changes in infiltrating immune cells and escape from CD8+ T-cell surveillance, effects largely driven by the poorly understood interferon epsilon. These results reveal a chromosomal deletion that disables both cell-intrinsic and cell-extrinsic tumor suppression and provide a framework for interrogating large deletions in cancer and beyond.
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Interferon cluster loss creates a cold tumor immune milieu and resistance to immunotherapy.
“Interferon cluster loss creates a “cold” tumor immune milieu and resistance to immunotherapy52”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [52]
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LncRNA ZFHX4-AS1 as a novel biomarker in adrenocortical carcinoma
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Ganguli, P., Basanta, C. D. L. A. C., Acha‐Sagredo, A., Mišetić, H., Armero, M., Mendez, A., Zahra, A., Devonshire, G., Kelly, G. P., Freeman, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.24.576991 · Cited by 2 · see citing works
Bergsma, P., Porazinski, S. R., Istadi, A., Fajardo, D. C., Mahmood, Y., Lombardi, S., Schuhmacher, D., Barraclough-Franks, H., Strbenac, D., Dennis, C. V., et al. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0704 · Cited by 1 · see citing works
Yuan, S., Hu, T., Yan, L., & Li, M. (2025) · Cancers · doi:10.3390/cancers17182983 · Cited by 1 · see citing works
Vanstraelen, S., Reiner, A., Tan, K. L., Mastrogiacomo, B., Dunne, E. G., Fick, C. N., Dycoco, J., Abass, A., Bott, M. J., Sánchez-Vega, F., et al. (2026) · International Journal of Cancer · doi:10.1002/ijc.70373 · Cited by 1 · see citing works
Lisitsa, D. A., Shindyapin, V. V., Nurislamov, A. R., Demidov, O. N., & Bogdanova, D. A. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1741704 · Cited by 1 · see citing works
Advancing precision medicine in pancreatic cancer using novel biomarkers and clinical targets
Murthy, D., Seyhan, A. A., den Hollander, P., Lu, S., Kuburich, N. A., Gould, C., Karam, A., Sun, K., Schupp, P. G., Safran, H., et al. (2026) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2026.101476 · Cited by 2 · see citing works
Jafari, Z., Nazhdi, Z. A., EmamAlizadeh, M., & Athari, S. S. (2026) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2026.106960 · Cited by 1 · see citing works
Pavlick, D. C., Rengarajan, S., Lee, J., Jin, D. X., Frampton, G. M., Fendler, B. J., Savol, A., Gjoerup, O. V., Tukachinsky, H., Huang, R. S. P., et al. (2026) · JCO Precision Oncology · doi:10.1200/po-26-00037 · Cited by 1 · see citing works
Investigating the Consequences of Aneuploidy in Cancer and Normal Tissue
Modi, J. N., & Taylor, A. M. (2026) · Advances in experimental medicine and biology · doi:10.1007/978-3-032-22637-2_15 · Cited by 1 · see citing works
Suwala, A. K., Friedel, D., Hinz, F. E., Mahlknecht, P., Schinkewitsch, S., Rieder, M., Fernandez, N. R., Stengs, L. K., Chang, Y., Ringel, A., et al. (2026) · Neuro-Oncology · doi:10.1093/neuonc/noag132 · Cited by 1 · see citing works
MTAP loss in non–small-cell lung Cancer and beyond: Therapeutic targeting of the MAT2A–PRMT5 axis
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Self-citationType I interferon signaling instills divergent metastatic phenotypes and immunotherapy responsesPreprint
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Studying large genomic deletions with MACHETE
Barriga, F. M. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00561-x
Self-citation
- Authors
- Barriga, F. M., Tsanov, K. M., Ho, Y.-J., Sohail, N., Zhang, A., Baslan, T., Wuest, A. N., Del Priore, I., Meškauskaitė, B., Livshits, G., Alonso-Curbelo, D., Simon, J., Chaves-Perez, A., Bar-Sagi, D., Iacobuzio-Donahue, C. A., Notta, F., Chaligne, R., Sharma, R., Pe’er, D., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Ontario Institute for Cancer Research (CA)
- Corresponding author
- Lowe, Scott W.
- ORCID
- Venue
- Nature Cancer
- Published
- 2022-11-07
- Volume
- 3
- Issue
- 11
- Pages
- 1367-1385
- ISSN
- 2662-1347 (ISSN-L)
- PMC
- PMC9701143
- OpenAlex
- W4308458365
- Cited by
- 125
- References
- 82
- Citations by year
- 2026: 28 · 2025: 35 · 2024: 40 · 2023: 21 · 2022: 1
- FWCI
- 9.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Howard Hughes Medical Institute (P30 CA08748)
- Jane Coffin Childs Memorial Fund for Medical Research
- Memorial Sloan-Kettering Cancer Center (P30-CA08748)
- Edward P. Evans Foundation
- Cycle for Survival
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology
- National Cancer Institute (T32CA160001, CA08748, P01CA013106, P30CA008748)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- chromosome 9p21.3, CDKN2A/B, homozygous deletion, interferon epsilon, immune evasion, metastasis, immunotherapy resistance, tumor microenvironment, type I interferon signaling, pancreatic cancer, machete, syngeneic mouse model, tumor suppressor inactivation
- MeSH terms
- Animals, Chromosome Deletion, Chromosomes, Interferons, Neoplasms, Tandem Repeat Sequences, Mice, Immune Evasion, Tumor Microenvironment
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