Epigenetic modification of CSDE1 locus dictates immune recognition of nascent tumorigenic cells

Weak immunogenicity of tumor cells is a root cause for the ultimate failure of immunosurveillance and immu-notherapy. Although tumor evolution can be shaped by immunoediting toward a less immunogenic phenotype, mechanisms governing the initial immunogenicity of primordial tumor cells or original cancer stem cells remain obscure. Here, using a single tumor-repopulating cell (TRC) to form tumors in immunodeficient or immunocom-petent mice, we demonstrated that immunogenic heterogeneity is an inherent trait of tumorigenic cells defined by the activation status of signal transducer and activator of transcription 1 (STAT1) protein in the absence of immune pressure. Subsequent investigation identified that the RNA binding protein cold shock domain-con-taining protein E1 (CSDE1) can promote STAT1 dephosphorylation by stabilizing T cell protein tyrosine phos-phatase (TCPTP). A methyltransferase SET and MYN domain-containing 3 (SMYD3) was further identified to mediate H3K4 trimethylation of CSDE1 locus, which was under the regulation of mechanotransduction by cell-matrix and cell-cell contacts. Thus, owing to the differential epigenetic modification and subsequent differ-ential expression of CSDE1, nascent tumorigenic cells may exhibit either a high or low immunogenicity. This identified SMYD3-CSDE1 pathway represents a potential prognostic marker for cancer immunotherapy effec-tiveness that requires further investigation.