Engineering an in vivo charging station for CAR-redirected invariant natural killer T cells to enhance cancer therapy.

Cancer immunotherapy is an emerging treatment approach that uses the body's immune system to recognize and destroy cancer cells. One promising strategy involves genetically engineering immune cells to better identify and attack tumors. Among these immune cells, invariant natural killer T (iNKT) cells are particularly attractive because they can naturally travel to tumors, recognize cancer-related signals, and potentially be used to develop treatments for multiple patients. By equipping these cells with specially designed receptors, known as chimeric antigen receptors (CARs), researchers can further enhance their ability to target cancer. However, a major challenge is that these engineered immune cells often become less active and fail to survive long enough within tumors, limiting their long-term effectiveness. To address this challenge, we developed an innovative system called the iNKT cell-targeted Microparticle Recruitment and Activation System (iMRAS). This technology uses tiny engineered particles that mimic some of the functions of natural immune-supporting cells. Acting like a local "charging station" for cancer-fighting immune cells, iMRAS releases signals that attract engineered iNKT cells to a specific location and provides stimulation to help them become more active, multiply, and survive longer. Our research demonstrates that iMRAS can strengthen the cancer-fighting abilities of engineered iNKT cells by creating a supportive environment that helps maintain their activity over time. In preclinical studies involving lymphoma and melanoma, two different types of cancer, this approach improved the persistence of engineered immune cells and their ability to control tumor growth. Unlike conventional approaches that primarily focus on modifying immune cells before introducing them into the body, iMRAS provides ongoing support to these cells after administration. This strategy may help address one of the major barriers to successful immunotherapy, particularly for solid tumors, where the surrounding environment can weaken immune cell function. Overall, our findings highlight the potential of iMRAS as a new approach to improving the effectiveness and durability of engineered immune cell therapies. By helping cancer-fighting cells reach tumors, remain active, and survive longer, this technology could contribute to the development of more effective cancer treatments. Further studies will be needed to evaluate its safety and effectiveness in humans.