Dual-targeted therapy shows promise against metastatic triple-negative breast cancer

A new preclinical study suggests that attacking triple-negative breast cancer (TNBC) in two ways at once can kill cancer cells, slow tumor growth and limit the cancer's spread. Researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) developed the approach. The findings could help guide new treatments for this hard-to-treat form of breast cancer.

This study points to a possible new way to fight TNBC by pairing a targeted 'smart bomb' drug with a treatment that shuts down the cancer cells' energy factories."

Xiaoguang "Margaret" Liu, PhD, study's corresponding author and member of the OSUCCC – James Translational Therapeutics Program

Liu also is a professor in Ohio State's College of Engineering. "These results are an early step. If the approach continues to work in laboratory studies and clinical trials, it could lead to a more effective treatment with fewer side effects than current options."

The findings were published Aug. 18, 2026, in Cell Reports Medicine. The study helps scientists better understand how triple-negative breast cancer may survive treatment. It suggests the cancer may be more vulnerable when one treatment delivers a drug directly to cancer cells and another cuts off their energy supply.

Why triple-negative breast cancer is difficult to treat

TNBC does not have estrogen or progesterone receptors and does not have high levels of the HER2 protein. Many breast cancer drugs work by targeting one of these features. Because TNBC lacks these targets, fewer targeted treatments are available. TNBC also is more likely to spread and return after treatment, which can lead to poorer long-term survival.

Two treatments attack cancer in different ways

Researchers combined two treatments that attack cancer in different ways. The first was an antibody-drug conjugate, or ADC, aimed at CD276, a protein on the surface of some cancer cells. The second was cmLumiOpto, a gene therapy that disrupts mitochondria, the structures that produce energy for cells.

The ADC links a laboratory-made antibody to an anticancer drug. The antibody recognizes a specific target on a cancer cell and carries the drug to it, potentially limiting damage to healthy cells. CmLumiOpto targets mitochondria to cut off the energy cancer cells need to survive.

In earlier work, the team developed antibodies that target CD276 and used them to build ADCs. Those treatments reduced the amount of cancer in preclinical models of TNBC and non-small cell lung cancer. The new study tested whether a CD276-targeted ADC could work against TNBC that had spread and whether adding another treatment could improve the results.

Combination slowed tumor growth and spread

In two preclinical research models of metastatic TNBC, the combination killed cancer cells, slowed tumor growth and reduced the cancer's spread more effectively than either treatment alone. The results suggest that attacking both CD276 and the cancer cells' energy supply may be a useful approach to study for advanced TNBC.

More research needed before human testing

The researchers caution that results from preclinical models do not always apply to people. These models also may not show everything that happens in human TNBC. Researchers still must find the best doses and treatment schedules. Future studies also must examine long-term safety, possible side effects and whether tumors can stop responding to the treatment.

"The lower-dose findings warrant further study because reducing the amount of treatment could help limit dose-related side effects," said senior co-author Lufang Zhou, PhD, a professor of surgery and biomedical engineering and a member of the OSUCCC – James Cancer Biology Research Program.

More laboratory research is needed to confirm the combination's benefits and safety before it can move to clinical trials. Next steps in this research are to secure funding to complete additional studies required before this technology can advance to clinical trials, while Ohio State works to identify a commercial partner for the technology. Separately, development of the licensed CD276-targeted antibody-drug conjugate is moving forward through studies and manufacturing needed to support a future clinical trial application.

Other Ohio State co-authors include: Tanvi Varadkar, Zhuoxin "Zora" Zhou, Yingnan Si, PhD, (now a scientist at Sanofi in Boston), Jiashuai Zhang, PhD; Zhantao Du, Anjana Gautam Khanal, Srijita Chowdhury, and Chandini Tsaliki. Funding support comes from the National Institutes of Health, National Cancer Institute and Pelotonia.