Study finds why immunotherapies don’t work on hardest-to-treat breast cancers
Thanks to advances in cancer therapies, most forms of breast cancer are highly treatable, especially when caught early.
But the last frontier cases — those that can’t be treated with hormone or targeted therapies and don’t respond to chemotherapy — remain the deadliest and hardest to treat. Tulane University researchers have discovered for the first time how these cancers persist after chemo and why they don’t respond well to immunotherapies designed to clear out remaining tumor cells by revving up the immune system.
The process of surviving chemotherapy triggers a program of immune checkpoints that shield breast cancer cells from different lines of attack by the immune system. It creates a “whack-a-mole” problem for immunotherapy drugs called checkpoint inhibitors that may kill tumor cells expressing one checkpoint but not others that have multiple checkpoints, according to a new study published in the journal Nature Cancer.
“Breast cancers don't respond well to immune checkpoint inhibitors, but it has never really been understood why,” said corresponding author James Jackson, associate professor of biochemistry and molecular biology at Tulane University School of Medicine. “We found that they avoid immune clearance by expressing a complex, redundant program of checkpoint genes and immune modulatory genes. The tumor completely changes after chemotherapy treatment into this thing that is essentially built to block the immune system.”
Researchers studied the process in mouse and human breast tumors and identified 16 immune checkpoint genes that encode proteins designed to inactivate cancer-killing T-cells.
“We’re among the first to actually study the tumor that survives post-chemotherapy, which is called the residual disease, to see what kind of immunotherapy targets are expressed,” said the study’s first author Ashkan Shahbandi, an M.D./Ph.D. student in Jackson's lab.
The tumors that respond the worst to chemotherapy enter a state of dormancy — called cellular senescence — instead of dying after treatment. Researchers found two major populations of senescent tumor cells, each expressing different immune checkpoints activated by specific signaling pathways. They showed the expression of immune evasion programs in tumor cells required both chemotherapy to induce a senescent state and signals from non-tumor cells.
They tested a combination of drugs aimed at these different immune checkpoints. While response could be improved, these strategies failed to fully eradicate the majority of tumors.
“Our findings reveal the challenge of eliminating residual disease populated by senescent cells that activate complex immune inhibitory programs,” Jackson said. “Breast cancer patients will need rational, personalized strategies that target the specific checkpoints induced by the chemotherapy treatment.”
This article first appeared in Tulane News. Read the original.
Enjoy reading ASBMB Today?
Become a member to receive the print edition four times a year and the digital edition monthly.
Learn moreGet the latest from ASBMB Today
Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.
Latest in Science
Science highlights or most popular articles

Understanding the roles of extracellular matrix and vesicles in valvular disease
MOSAIC scholar Cassandra Clift uses mass spectrometry and multiomics to study cardiovascular calcification and collagen dysregulation, bridging her background in bioengineering and biology to investigate extracellular vesicles and heart disease.

Lipid profiles reveal sex differences in type 2 diabetes
Researchers explored the lipid profiles of individuals with type 2 diabetes and identified potentially useful lipid biomarkers for this condition.

Serum lipids may predict early diabetes risk
Researchers found that levels of two key fatty acids may predict worsening tolerance for glucose, independent of body fat and insulin levels. In turn, these fatty acids may serve as early T2D biomarkers.

Sex and diet shape fat tissue lipid profiles in obesity
Researchers found that sex hormone levels and diet both influence inflammation and lipid composition in obesity.

Mapping the placenta’s hormone network
Study uncovers how the placenta actively metabolizes not only glucocorticoids but also novel androgens and progesterones, reshaping our understanding of pregnancy and its complications.

Biochemists and molecular biologists sweep major 2025 honors
Recent Nobel, MacArthur and Kimberly Prize honorees highlight the power of biochemistry and molecular biology to drive discovery, including immune tolerance, vaccine design and metabolic disease, and to advance medicine and improve human health.