Detection of cell–cell interactions via photocatalytic cell tagging

The growing appreciation of immune cell–cell interactions within disease environments has led to extensive efforts to develop immunotherapies. However, characterizing complex cell–cell interfaces in high resolution remains challenging. Thus, technologies leveraging therapeutic-based modalities to profile intercellular environments offer opportunities to study cell–cell interactions with molecular-level insight. We introduce photocatalytic cell tagging (PhoTag) for interrogating cell–cell interactions using single-domain antibodies (VHHs) conjugated to photoactivatable flavin-based cofactors. Following irradiation with visible light, the flavin photocatalyst generates phenoxy radical tags for targeted labeling. Using this technology, we demonstrate selective synaptic labeling across the PD-1/PD-L1 axis in antigen-presenting cell–T cell systems. In combination with multiomics single-cell sequencing, we monitored interactions between peripheral blood mononuclear cells and Raji PD-L1 B cells, revealing differences in transient interactions with specific T cell subtypes. The utility of PhoTag in capturing cell–cell interactions will enable detailed profiling of intercellular communication across different biological systems.