scIRES-seq reveals multimodal molecular heterogeneity in CTCs from small cell cervical cancer

scIRES-seq, a new single-cell framework linking immunophenotype, genetic variation, DNA methylation and gene expression, was coupled to real-time imaging spectral flow cytometry and applied to circulating tumor cells from a patient with metastatic cervical small cell neuroendocrine carcinoma. Tumor-matched copy-number alterations and targeted somatic variants established CTC identity, and methylation profiles matched metastatic tissue. Genetic and methylation analyses identified two CTC subpopulations that transcriptomes alone did not distinguish, showing the value of multi-omics profiling of rare cells.