Cytokines Linked With Drug Resistance in Ovarian Cancer, but Underlying Mechanisms Remain Unclear

Cytokines are believed to play a key role in treatment resistance in patients with ovarian cancer, according to a new review article published in the International Journal of Cancer, but the exact role and mechanisms behind it have remained obscure.1

Corresponding author Jingjing Li, PhD, of the University of Chicago Medical Center, and colleagues began by noting that ovarian cancer sits at a frustrating paradox. It is the leading cause of death among patients with cancers of the female reproductive system, making it a research priority. Yet, very little progress on ovarian cancer treatment has been made in recent years, the authors said.

Most patients with ovarian cancer are given platinum-based chemotherapy as their first-line therapy, often in combination with paclitaxel (Taxol; Bristol-Myers Squibb). Poly(ADP-ribose) polymerase inhibitors are widely used as maintenance therapy for patients with advanced cancers, they added. Those treatments can be effective, but 80% of patients will relapse after chemotherapy, and 75% of those patients will have drug-resistant cancer upon relapse.2,3

A new review article examines how multidrug combinations may counteract the role of cytokines in drug resistance. | Image Credit: tashatuvango - stock.adobe.com

“The mechanisms of drug resistance are rather complex and can include, but are not limited to, dysfunction of influx and efflux transporters, tubulin isotype compensation, metabolic reprogramming, phosphoinositide 3-kinase/protein kinase B (PI3/AKT) pathway hyperactivation, and cisplatin-induced autophagy,” they wrote.1

However, the researchers added that cytokines, including IL-6 and IL-8, transforming growth factor-beta, vascular endothelial growth factor, and epidermal growth factor receptor, have also been widely investigated because their secretion by immune cells is associated with a complex tumor microenvironment.

Prior research on the potential role of cytokines found that IL-6 signaling can reprogram and alter T-cell immune responses to tumors. IL-6 may also be a biomarker to distinguish between malignant and non-malignant lesions and potentially to predict chemoresistance.

IL-11 is generally expressed at a very low level, the researchers noted, but expression levels increase significantly during inflammatory responses or carcinogenesis. They added that elevated IL-11 has been linked with tumor grade in bladder cancer. Further evidence from gastric cancer models suggests that targeting IL-11-mediated pathways may help overcome drug resistance in clinical practice.

As for the potential of using anti-inflammatory phytochemicals as chemotherapy sensitizers, the researchers explained that several phytochemicals have been shown to act on drug-resistant ovarian cancer cells by enhancing apoptosis-related pathways and inhibiting the secretion of proinflammatory cytokines. Thus, phytochemicals improve therapeutic response when used alongside clinical first-line drugs. For instance, the synthetic triterpenoid CDDO-Me has been shown to partially reverse drug resistance phenotypes of ovarian cancer.4

The soy isoflavone genistein has also been studied as a potential remedy for drug resistance and may be a promising synergistic drug in combination therapy, the authors said.1

The investigators summarized their review by highlighting the complexity of the mechanisms by which cytokines play a role in drug resistance. As a result, overcoming drug resistance will likely be dependent upon personalizing targeted therapy, they said.

“At the same time, it is necessary to integrate databases to find commonalities to escort the treatment,” the authors wrote. “When evaluating patients receiving chemotherapy, single inhibition cannot block the influence of cytokines on the drug-resistance mechanism, so the emergence of multi-targeted drugs is necessary.”

In the same way, they concluded by underscoring that solving the broader problem of drug resistance in ovarian cancer will require the integration of diverse resources.

References

1. Wang L, Zang Y, Dejenie R, et al. The role of cytokines in ovarian cancer drug resistance. Int J Cancer. Published online September 19, 2025. doi:10.1002/ijc.70099
2. Laganà AS, Sofo V, Vitale SG, Triolo O. Epithelial ovarian cancer inherent resistance: May the pleiotropic interaction between reduced immunosurveillance and drug-resistant cells play a key role?. Gynecol Oncol Rep. 2016;18:57-58. doi:10.1016/j.gore.2016.09.004
3. Khan MA, Vikramdeo KS, Sudan SK, et al. Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management. Semin Cancer Biol. 2021;77:99-109. doi:10.1016/j.semcancer.2021.08.005
4. Duan Z, Ames RY, Ryan M, Hornicek FJ, Mankin H, Seiden MV. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemother Pharmacol. 2009;63(4):681-689. doi:10.1007/s00280-008-0785-8