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SMYD3 Promotes Immune Evasion in Clear Cell Renal Cell Carcinoma via SREBP1-Mediated Transactivation of CD47

Zhengfang Liu1,2,3, Xiumei Zhao4, Maolin Zang2

  • 1Thoracic Surgery Department, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, 250117, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 23, 2025
PubMed

Insights

Dysregulation of SMYD3 in clear cell renal cell carcinoma (ccRCC) creates an immunosuppressive tumor microenvironment. This impairs PD-1 blockade response by promoting T helper 2 cell infiltration via the SMYD3-SREBP1-CD47 axis.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Cancer cell-intrinsic features significantly influence the tumor immune microenvironment and immunotherapy response.
  • Clear cell renal cell carcinoma (ccRCC) exhibits complex interactions between tumor cells and immune cells.
  • Understanding these interactions is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the role of SET and MYND domain-containing protein 3 (SMYD3) in ccRCC immunity.
  • To elucidate the molecular mechanisms by which SMYD3 regulates the tumor immune microenvironment.
  • To identify potential therapeutic targets for enhancing immunotherapy in ccRCC.

Main Methods:

  • Analysis of cancer cell-intrinsic features and immune cell infiltration in ccRCC.
  • Investigating the interaction between SMYD3, Sp1, sterol regulatory element-binding protein 1 (SREBP1), and CD47.
  • Assessing the impact of the SMYD3-SREBP1-CD47 axis on T helper 2 cell infiltration and PD-1 blockade response.

Main Results:

  • Dysregulated SMYD3 orchestrates an immunosuppressive microenvironment in ccRCC.
  • SMYD3 cooperates with Sp1 to upregulate SREBP1 and subsequently CD47 expression.
  • The SMYD3-SREBP1-CD47 axis promotes T helper 2 cell infiltration, hindering anti-tumor immunity and PD-1 blockade efficacy.

Conclusions:

  • The SMYD3-SREBP1-CD47 axis is a critical regulator of the immune microenvironment in ccRCC.
  • Targeting this axis offers a potential strategy to enhance anti-tumor immunity and improve immunotherapy outcomes in ccRCC.
Keywords:
SMYD3/SREBP1/CD47 signalingclear cell renal cell carcinomaimmune evasion

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