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

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.