Turning Cancer Cells’ ‘Softness’ Against Them: Technology Developed to Trigger Immune Attack

U.S. researchers have developed a technology that exploits the physical “softness” of cancer cells to prompt immune cells to attack them. The approach is drawing attention as a potential way to overcome a key obstacle that limits the effectiveness of CAR-T cell therapy in solid tumors.

According to BioOn on the 29th (local time), a research team from the USC Viterbi School of Engineering and Keck School of Medicine designed a genetic tool that turns soft cancer cells into targets. The findings were published in the international journal Nature Biomedical Engineering.

CAR-T cell therapy involves equipping a patient’s T cells with receptors that recognize cancer cells, enabling them to attack the cancer. The therapy has demonstrated efficacy in blood cancers, but its results in solid tumors have been limited.

The team viewed the physical environment of tumors, particularly its softness, as a factor that hinders CAR-T cell success. Cancer cells in soft environments have properties similar to those of stem cells and are resistant to treatment, the researchers said.

Jenny Yoonjia Choi, Ph.D., the paper’s first author, explained, “CAR-T cells grab and kill hard cells, but miss cells that are as soft as jelly.” Peter Yingxiao Wang, a professor, added, “Soft cells are difficult to grab, which reduces killing efficiency.”

To address this immune evasion, the team created a genetic tool called a “mechano-recorder.” It acts like a “black box” that records the mechanical softness a cell experiences. Taking advantage of the sharp increase in calcium signaling in soft cancer cells, the tool converts transient calcium signals into persistent fluorescent signals, leaving a barcode in the cells.

The team then replaced the fluorescent marker with the CD19 antigen for therapeutic use. CD19 is an antigen validated in CAR-T treatment for blood cancers. When soft cancer cells express CD19, CAR-T cells recognize it as an “attack signal” and destroy them.

Dr. Choi said, “When soft cells express this signal, CD19 CAR-T cells selectively attack those cells.”

In experiments using breast cancer cell lines, patient-derived cells and mouse models, the strategy overcame resistance in soft, cancer stem cell-like cells. Although the reprogrammed tumors were softer, T-cell infiltration and killing efficiency increased.

Professor Wang predicted that the technology could be extended beyond breast cancer to all solid tumors. The team has already tested the approach in glioblastoma, pancreatic cancer and prostate cancer models.

Professor Wang said, “Any molecular signaling pathway we detect can be converted into an ‘attack signal’ or a ‘help signal,’ as needed.”