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

ABSTRACT: The field of immunotherapy for clear cell renal cell carcinoma (ccRCC) is rapidly expanding over the past decade, but limited success to date. 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. CD47, a bridge between innate and adaptive immunity, acted as the downstream effector molecule of the SMYD3 signal to promote the infiltration of Th2 cells, protecting renal cancer cell from immune attack. In summary, we elucidated a critical role for cancer cell-intrinsic SMYD3-SREBP1-CD47 signal in the regulation of the immune microenvironment in ccRCC, and provided a potential strategy to manipulate the tumor immune milieu in favor of antitumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE261853 | GEO | 2026/03/15

REPOSITORIES: GEO

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