Beyond the Transcriptome: Leveraging Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) for Deeper Cellular Insights

The advent of single-cell genomics has revealed profound cellular heterogeneity, yet transcriptomic profiling alone often fails to show the functional proteomic state of a cell. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) emerged to bridge this critical gap, enabling the simultaneous quantification of RNA and surface protein expression within individual cells. This transformative technology leverages oligonucleotide-conjugated antibodies to assess protein abundance using a panel of marker-specific tags, which are cocaptured with cellular messenger RNA in single-cell sequencing workflows. This review details the methodological principles of CITE-seq, its compatibility with diverse sequencing platforms, and the computational frameworks required for integrated data analysis. We highlight its impact on cell biology, oncology, and infectious disease research, where it has refined cell classification, dissected tumor microenvironments, and decoded host-pathogen interactions. Finally, we discuss persistent technical and computational challenges and outline future directions, including spatial integration and predictive modeling, positioning CITE-seq as a cornerstone of next-generation biomedical discovery.