Read online: https://www.sciencedirect.com/science/article/pii/S0142961223001096

Abstract

Immunotherapy, despite its promise for future anti-cancer approach, faces significant challenges, such as off-tumor side effects, innate or acquired resistance, and limited infiltration of immune cells into stiffened extracellular matrix (ECM). Recent studies have highlighted the importance of mechano-modulation/-activation of immune cells (mainly T cells) for effective caner immunotherapy. Immune cells are highly sensitive to the applied physical forces and matrix mechanics, and reciprocally shape the tumor microenvironment. Engineering T cells with tuned properties of materials (e.g., chemistry, topography, and stiffness) can improve their expansion and activation ex vivo, and their ability to mechano-sensing the tumor specific ECM in vivo where they perform cytotoxic effects. T cells can also be exploited to secrete enzymes that soften ECM, thus increasing tumor infiltration and cellular therapies. Furthermore, T cells, such as chimeric antigen receptor (CAR)-T cells, genomic engineered to be spatiotemporally controllable by physical stimuli (e.g., ultrasound, heat, or light), can mitigate adverse off-tumor effects. In this review, we communicate these recent cutting-edge endeavors devoted to mechano-modulating/-activating T cells for effective cancer immunotherapy, and discuss future prospects and challenges in this field.