Mechanical Immunoengineering of T cells for Therapeutic Applications.

T cells, a key component in adaptive immunity, are central to many immunotherapeutic modalities aimed at treating various diseases including cancer, infectious diseases, and autoimmune disorders. The past decade has witnessed tremendous progress in immunotherapy, which aims at activation or suppression of the immune responses for disease treatments. Most strikingly, cancer immunotherapy has led to curative responses in a fraction of patients with relapsed or refractory cancers. However, extending those clinical benefits to a majority of cancer patients remains challenging. In order to improve both efficacy and safety of T cell-based immunotherapies, significant effort has been devoted to modulating biochemical signals to enhance T cell proliferation, effector functions, and longevity. Such strategies include discovery of new immune checkpoints, design of armored chimeric antigen receptor (CAR) T cells, and targeted delivery of stimulatory cytokines and so on.Despite the intense global research effort in developing novel cancer immunotherapies, a major dimension of the interactions between cancer and the immune system, its biomechanical aspect, has been largely underappreciated. Throughout their lifecycle, T cells constantly survey a multitude of organs and tissues and experience diverse biomechanical environments, such as shear force in the blood flow and a broad range of tissue stiffness. Furthermore, biomechanical properties of tissues or cells may be altered in disease and inflammation. Biomechanical cues, including both passive mechanical cues and active mechanical forces, have been shown to govern T cell development, activation, migration, differentiation, and effector functions. In other words, T cells can sense, respond to, and adapt to both passive mechanical cues and active mechanical forces.Biomechanical cues have been intensively studied at a fundamental level but are yet to be extensively incorporated in the design of immunotherapies. Nonetheless, the growing knowledge of T cell mechanobiology has formed the basis for the development of novel engineering strategies to mechanically modulate T cell immunity, a nascent field that we termed "mechanical immunoengineering". Mechanical immunoengineering exploits biomechanical cues (e.g., stiffness and external forces) to modulate T cell differentiation, proliferation, effector functions, etc., for diagnostic or therapeutic applications. It provides an additional dimension, complementary to traditional modulation of biochemical cues (e.g., antigen density and co-stimulatory signals), to tailor T cell immune responses and enhance therapeutic outcomes. For example, stiff antigen-presenting matrices have been shown to enhance T cell proliferation independently of the intensity of biochemical stimulatory signals. Current strategies of mechanical immunoengineering of T cells can be categorized into two major fields including passive mechanical cue-oriented and active force-oriented strategies. In this Account, we first present a brief overview of T cell mechanobiology. Next, we summarize recent advances in mechanical immunoengineering, discuss the roles of chemistry and material science in the development of these engineering strategies, and highlight potential therapeutic applications. Finally, we present our perspective on the future directions in mechanical immunoengineering and critical steps to translate mechanical immunoengineering strategies into therapeutic applications in the clinic.