Researchers at the USC Viterbi School of Engineering and Keck School of Medicine of USC have engineered a remarkable genetic tool that addresses one of the most persistent obstacles in cancer immunotherapy: the physical softness of tumors. The work, detailed in the journal Nature Biomedical Engineering, reveals how the soft environment of a tumor enables cancer cells to become “stealthy” and resistant to treatment, providing a powerful new mechanism to tag those evasive cells for destruction. The paper’s lead author, Jenny Yunjia Qu, a postdoctoral researcher in the lab of Peter Yingxiao Wang, the Dwight C. and Hildagarde E. Baum Department Chair in the Alfred Mann Department of Biomedical Engineering, collaborated with the USC Viterbi and Keck School of Medicine teams to develop a technique that successfully targets hard-to-reach “cancer stem-like cells.” These cell types possess stem cell-like abilities, including self-renewal, which make them key drivers of tumor growth, drug resistance, and cancer recurrence. CAR T therapy has revolutionized the treatment of blood cancers, but it struggles against solid tumors. The Wang Lab team has demonstrated the critical role of the physical microenvironment of a tumor in the success of CAR T-cells, particularly when that microenvironment is soft. To address this immune evasion, the research team first needed a way to identify and track these evasive soft cells. They engineered a genetic tool called the Mechano-Recorder, which acts like a “black box” inside the cell. The tool records the level of mechanical softness the cell experiences. The researchers discovered that softer cancer cells displayed significantly higher intracellular calcium signaling. The Mechano-Recorder converts this transient calcium signal into a stable, long-lasting fluorescent signal, effectively barcoding these cells with their mechanical experience. The team then successfully used this recorder to show that soft environments specifically promote these recorder-positive cells, which exhibit stem-cell-like features, including markers associated with metastasis and hypoxia. The researchers then leveraged the Mechano-Recorder’s design for therapeutic action, genetically reprogramming the system to convert the signature of soft, resistant cells into a targetable beacon for immune cell attack. Tested in breast cancer cell lines, patient-derived cells, and mouse models, the rewiring strategy successfully overcame the resistance of soft cancer stem-like cells. The results showed that these reprogrammed tumors, though softer, exhibited greater T-cell infiltration and enhanced killing efficacy.
