Mechanical sensing and reprogramming of CAR-engineered lymphocytes for next-generation ACT cancer immunotherapy

Objective

Adoptive cell transfer (ACT) with cytotoxic lymphocytes, including chimeric antigen receptor (CAR)-T cells, is a powerful immunotherapy already demonstrating remarkable success against certain blood cancers. However, its efficacy in treating solid tumors remains limited, with durable responses being rare. Current strategies to improve ACT therapy focus predominantly on biochemical interactions between immune cells and cancer cells. Yet, emerging evidence highlights the significant influence of biomechanical cues in shaping immune responses and therapeutic outcomes. For instance, the mechanical properties of cancer cells, such as cellular softness, can confer resistance to immune cell-mediated killing, while rigidifying cancer cells can sensitize them toward immune attack leading to enhanced immunotherapy. MechanoCAR explores a novel, under-explored approach: mechanical reprogramming of cytotoxic lymphocytes, including CAR-T and CAR natural killer (NK) cells. We hypothesize that enhancing the mechano-sensitivity of the lymphocytes could overcome some of the key limitations of ACT therapies, particularly against resistant tumors. First, we aim to uncover and characterize the mechano-sensing and mechano-transduction mechanisms of CARs. Next, we will develop and test innovative mechanical reprogramming strategies to enhance the cytotoxic potential of CAR-T/NK cells in advanced tumor models and further explore the therapeutic potential using patient-derived organoids. This ambitious and high-reward research has the potential to transform ACT cancer immunotherapy. It addresses significant gaps in current biochemical-centric approaches by introducing a new paradigm focusing on mechanical modulation. If successful, it will provide groundbreaking insights into mechano-immunology, offer a blueprint for designing the next-generation ACT immunotherapies, and ultimately improve treatment outcomes for patients with challenging cancers.