SMYD3 promotes immune evasion in clear cell renal cell carcinoma via SREBP1-mediated transactivation of CD47

Cancer cell-intrinsic features (e.g., genetic aberrations, dysregulation of signaling pathway) play a pivotal role in orchestrating the composition and functional state of immune landscape, which in turn impact tumor progression and response to immunotherapy. However, the underlying mechanism of crosstalk between renal cancer cell and immune cell is largely unknown.

Here we discovered that cancer cell-intrinsic SET and MYND domain-containing protein 3 (SMYD3) dysregulation orchestrated an immunosuppressive microenvironment and impaired responses to PD-1 blockade by reprograming the infiltration of immune cells in tumor microenvironment (TME) of ccRCC. Mechanistically, SMYD3, a chromatin regulator, cooperated with Sp1 to transcriptionally promote sterol regulatory element-binding protein 1 (SREBP1) expression by modifying H3-K4 di-/trimethylation and consequently activating the transcription of CD47.