New immune mechanism helps explain why ovarian cancer stops responding to chemotherapy
· Medical Xpressedited by Sadie Harley, reviewed by Robert Egan
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Scientists at The Wistar Institute have identified a new mechanism behind the chemotherapy resistance that makes ovarian cancer so lethal. In a new study published in The Journal for ImmunoTherapy of Cancer, the researchers show that chemotherapy triggers an inflammatory cascade that recruits immune cells into the tumor microenvironment, which ultimately function to protect the cancer from subsequent chemotherapy.
This finding could improve outcomes for patients because the molecular pathway the researchers discovered has the potential to be blocked using drugs already in clinical use for other diseases.
"Traditionally, chemotherapy resistance has been seen as a cancer-cell problem," said Nan Zhang, Ph.D., assistant professor in the Ellen and Ronald Caplan Cancer Center's Molecular and Cellular Oncogenesis Program and senior author of the study.
"Our findings suggest it is also an immunology problem. The treatment meant to kill the tumor can trigger inflammatory responses that help it survive. The encouraging news is that there are already approved drugs that may be able to target this pathway and restore chemotherapy sensitivity."
Looking beyond cancer cells
High-grade serous carcinoma is the most common and deadly subtype of ovarian cancer. Many patients initially respond to first-line chemotherapy, but the majority go on to develop recurrent disease that resists subsequent chemotherapy.
Although tumor-intrinsic genomic, epigenomic and transcriptional alterations contribute to chemoresistance, prior research has found limited genomic divergence between primary and recurrent tumors, suggesting that chemoresistance is also acquired through microenvironmental mechanisms.
As a result, researchers such as Zhang look beyond the cancer cells themselves to the surrounding tumor microenvironment for answers.
IL-1β points to immune protection
For this study, Zhang, Taito Miyamoto, Yujie Ye, Marlaine Soliman and their Wistar colleagues collaborated with gynecologic pathologists at the Kyoto University Graduate School of Medicine to investigate recurring chemoresistance in ovarian cancer patients. Using publicly available data sets, the researchers compared patient tumor samples before and after chemotherapy.
They found that interleukin-1 beta (IL-1β), a protein the body releases to signal the immune system to "send help" and promote inflammation, was significantly elevated after chemotherapy, particularly in patients whose tumors didn't respond well to chemotherapy.
To test IL-1β's significance, the researchers used genetically engineered murine models lacking the ability to produce or respond to IL-1β. When treated with chemotherapy, these models' tumors shrank, while models with normal immune systems remained resistant to treatment.
Tracing the pathway further, the team postulated that when IL-1β binds to structural cells within tumors, it triggers the release of a chemical signal that attracts a type of white blood cell called neutrophils. Once recruited, the neutrophils protect tumors by exhausting cancer-fighting T cells and by undergoing a process called NETosis, in which the neutrophils rupture and release web-like structures called neutrophil extracellular traps (NETs).
In the lab, the team found that NETs reduced the effectiveness of chemotherapy drugs on cancer cells and that blocking NET formation restored the drugs' effectiveness. In tumor samples from ovarian cancer patients, the researchers observed that both neutrophil infiltration and NET formation increased after chemotherapy, mirroring what they saw in preclinical models.
Paths toward combination treatment
Building on these preclinical findings, Zhang, Soliman and their colleagues are now exploring whether interrupting this pathway could eventually be translated into a clinical strategy to counter chemotherapy resistance.
"IL-1β therapies are already out there, and some are actually clinically approved for other conditions. So there is potential for these to be leveraged in this new context," said Marlaine Soliman, a third-year doctoral student in the Immunology Graduate Group at the University of Pennsylvania who is conducting her thesis research in the Zhang laboratory at The Wistar Institute and is a co-author of the study.
The researchers also see a possible opening for combination approaches involving immune checkpoint inhibitors, which reawaken T cells. If T cell suppression by neutrophils turns out to be a major contributor to chemoresistance, pairing checkpoint inhibitors with IL-1β-targeted therapy could offer another route to restoring chemotherapy's effectiveness.
Key questions still unresolved
Several questions remain open. The team doesn't yet know what specifically triggers the increase in IL-1β production in response to chemotherapy, nor exactly how NETs impair drug sensitivity at the molecular level.
Soliman, who is continuing this work as part of her doctoral research, is now investigating both avenues, along with whether T cells in this setting become truly exhausted and whether checkpoint inhibitors could reverse that.
"It's important to recognize that this is a complex tumor microenvironment, and this pathway is likely not the only reason patients experience chemoresistance," Soliman said. "But if you can significantly reduce resistance, that's important. At the end of the day, it's about how patients who have already gone through treatment once could get through it again if their cancer recurs, but with even better outcomes."
Publication details
Taito Miyamoto et al, Chemotherapy induces an IL1β-dependent neutrophil recruitment and activation that promote chemoresistance in metastatic ovarian cancer, Journal for ImmunoTherapy of Cancer (2026). DOI: 10.1136/jitc-2025-014253
Journal information: Journal for ImmunoTherapy of Cancer
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OncologyAllergy and immunologyObstetrics & gynecology Provided by The Wistar Institute Who's behind this story?
Sadie Harley
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