ATP‐Inducible Receptor Oligomerization Enables Fine‐Tuning of T Cell Immunity

Abstract Receptor oligomerization plays a pivotal role in the regulation of cellular behaviors and functionalities. Stimuli‐responsive artificial circuits are often programmed to rewire cell signaling by fine‐tuning receptor interactions through targeted stimulation. Notably, the integration of tumor microenvironment (TME)‐responsive systems capable of locally altering cancer cell phenotypes or transforming anti‐tumor responses of immune cells offers a novel and promising strategy for enhancing the therapeutic effectiveness and safety of cancer treatments. In this paper, we introduce an adenosine triphosphate (ATP)‐inducible receptor oligomerization (ATIRO) approach to facilitate the clustering of CD3 and CD8 of T cells and the engagement of CD3 and tumor markers of T cells and targeted cancer cells to prompt anti‐tumor immunity. ATIRO enables the specific in situ activation of T cells by the high‐level ATP presented in TME, thereby effectively suppressing tumor growth in vivo. ATIRO presents a versatile and readily adaptable strategy for the in‐situ reconfiguration of T cell immunity, holding significant potential for advancing cancer therapeutic interventions.