Immune synapse in the tumor microenvironment: functional dynamics and clinical translational perspectives

Immune synapse (IS) is a dynamic supra-molecular structure between immune cells and antigen-presenting cells (APCs) or other target cells. Through precise spatiotemporal organization, the IS integrates antigen recognition, signal amplification, and effector function, and is thereby associated with, and may contribute to the initiation, intensity, and durability of antitumor immune responses. Within the tumor microenvironment (TME), however, the structural integrity and signaling function of the IS are frequently disrupted by molecular, metabolic, physical, and epigenetic abnormalities, which may represent an important barrier to effective immunotherapy. This review dissects the regulation of IS in tumors from a multiscale perspective. At the molecular level, we discuss the LFA-1/ICAM-1 adhesion axis, co-stimulatory/co-inhibitory signals, neuroimmune crosstalk, and supramolecular assembly driven by liquid–liquid phase separation. At the physical level, we address the roles of matrix stiffness, tumor cell membrane mechanics, and mechanotransduction in IS assembly and effector function. At the metabolic and post-translational levels, we summarize how glycosylation remodeling, cholesterol metabolism, lactate accumulation, and adenosine signaling induce the synaptic signaling activation and cytoskeletal reorganization. We further summarize IS-targeted therapeutic strategies, including adhesion molecule agonists, immune checkpoint blockade, synaptic remodeling of engineered immune cells, metabolic modulation, and nanoengineering, and evaluate their translational potential and limitations. Finally, we propose that a paradigm shift from “repairing the synapse” to “programming the synapse”—by integrating biochemical signals, biophysical properties, and neuroimmune regulation to achieve precise and reversible control of IS function—may overcome current barriers in solid tumor immunotherapy and provide a conceptual framework for IS-guided precision immunotherapy.