UC Irvine

Cancer metastasis is the major cause of cancer death and remains mostly incurable. Recently, immunotherapy using chimeric antigen receptor-modified patients’ T cells (CAR-T cells) has shown tremendous promise in cancer treatment. Unfortunately, major toxic effects, such as cytokine release syndrome (CRS) and “on-target off-tumor” (OTOT) attack on normal tissue are frequently associated with CAR-T cell treatments. To overcome these severe side effects, we present a mechano-responsive immune cell system that can improve the targeting specificity and control the activation level of cell therapy. Our novel system utilizes both mechanical properties and tumor antigens that are specific to the metastatic tumor niche to trigger a two-keyed lock switch for CAR expression. Multiple mechanosensitive promoters were synthesized and characterized to induce CAR expression in response to specific mechanical cues in vitro. Our study demonstrates that our mechano-responsive immune cell system is specific and cytotoxic to antigen-associated cancer cells present within the stiffness range of the tumor microenvironment in Jurkat T cells and THP-1 derived macrophages models in vitro. This inducible immune cell system could reduce non-specific activation of immune cells, which lowers the OTOT side effects of current immune cell-based therapeutics. Our mechano-responsive immune cell system serves as a novel approach for immunotherapy to target aberrant tissue stiffness in the treatment of cancer metastases or even other fibrotic diseases.