Cancer-derived IGKC Suppresses Interferon Signaling and Promotes Tumor Metastasis

Immunoglobulins (Igs) have traditionally been recognized for their role in antibody production by B cells. However, their expression in cancer cells and their contributions to tumorigenesis and disease progression remain poorly understood. In this study, using single-cell resolution analysis, we identified a distinct subset of tumor cells with high immunoglobulin gene expression, particularly IGKC, which was significantly enriched in metastatic tumors. The overexpression of IGKC in metastatic tumors was further validated by in situ hybridization across multiple types of clinical tumor samples. Integrated analyses of whole-genome and transcriptome sequencing from pan-cancer cell lines in the CCLE revealed that, beyond B‑cell lymphomas, a subset of tumor cells from most carcinoma types also overexpress IGKC. Unlike in the B‑cell lineage, IGKC expression in tumor cells is driven by alternative splicing, generating fusion transcripts rather than the conventional DNA rearrangements seen in B cells. CUT&Tag and RNA sequencing demonstrated that IGKC transcription is directly regulated by TFAP2C, a transcription factor highly expressed in tumors and associated with poor prognosis. Mechanistically, IGKC interacts with hnRNPM, reducing the accumulation of double-stranded RNA, suppressing interferon responses, and ultimately promoting metastatic progression. In vivo, IGKC overexpression markedly accelerated tumor progression in multiple mouse models. Together, these findings identify tumor-derived IGKC as a key driver of metastasis and highlight the TFAP2C–IGKC–hnRNPM axis as a promising target for prognostic assessment and therapeutic intervention in metastatic cancer.