CAREER: Mechanisms of Tumor Growth-Induced Immunomechanical Dysfunction

The immune system plays a critical role in protecting the body from disease. However, in the context of cancer, the immune system becomes ineffective at recognizing and eliminating tumor cells. One important and often overlooked reason for this failure is that tumors pose not only biological but also physical challenges. As tumors grow, they generate crowding and pressure that physically squeeze nearby cells and disrupt how they function. With brain tumors, the skull limits how much the tissue can expand and amplifies these forces. This Faculty Early Career Development Program (CAREER) project investigates how these physical forces interfere with the ability of immune cells to find and destroy cancer cells, ultimately allowing tumors to grow unchecked. By uncovering how mechanical forces disrupt the immune system, this work addresses a fundamental gap in understanding how biology and physics interact in human health. The outcomes have broad implications for improving our understanding of cancer and immunity, guiding the design of new therapies, and advancing national priorities in biotechnology, health, and biomedical innovation. The project also includes integrated educational and training programs that engage students across multiple levels, providing research experiences and fostering multidisciplinary skills. These efforts will help prepare a capable workforce to address complex biomedical challenges. This research will establish fundamental principles of how compressive mechanical forces regulate immune cell fate and function in the tumor microenvironment. The central hypothesis is that growth-induced compressive forces directly impair the ability of anti-tumor immune cells to recognize and eliminate cancer cells. To test this, the project will combine engineered model systems spanning multiple scales, including cellular systems, organotypic brain models, and animal models of disease. Mechanical compression mimicking tumor growth will be precisely applied while immune cell function is evaluated through measurements of antigen presentation and recognition, cytotoxic function, and inflammatory signaling. Advanced imaging and molecular profiling techniques, including single-cell and spatial analyses, will be used to quantify changes in cell behavior and gene expression, and data-driven and machine learning approaches will integrate these datasets to identify mechanical mechanisms. By linking mechanical forces to immune dysfunction, this work will generate new mechanistic insights into immunomechanics and how tissue-scale forces influence immune cell behavior. In parallel, this project integrates research and education by developing multidisciplinary training programs, research experiences, and outreach activities that will expand participation in engineering and biomedical sciences. These advances will contribute foundational knowledge to biomechanics and mechanobiology and support national priorities in biotechnology, health, and workforce development. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2542492 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Meenal Datta | Institution: University of Notre Dame, NOTRE DAME, IN | Award Amount: $555,135 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2542492 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2542492.html