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Targeting tumor-intrinsic STK40 induces immune vulnerability and drives T cell reinvigoration

Lili Zhu1, Sisi Zhang1, Botai Li2

  • 1State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Cancer Cell
|May 28, 2026
PubMed

Insights

Researchers discovered serine/threonine kinase 40 (STK40) regulates immune evasion in liver cancer. Inhibiting STK40 enhances immunotherapy, leading to tumor regression and improved T cell responses.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immunotherapy has transformed cancer care but faces limited success in hepatocellular carcinoma (HCC).
  • Mechanisms underlying resistance to immunotherapy in HCC are not well understood.
  • Identifying novel targets is crucial for improving HCC treatment outcomes.

Purpose of the Study:

  • To identify novel regulators of immune evasion in hepatocellular carcinoma.
  • To investigate the role of serine/threonine kinase 40 (STK40) in HCC immune evasion.
  • To evaluate STK40 as a therapeutic target for enhancing anti-tumor immunity.

Main Methods:

  • In vivo CRISPR-Cas9 screening was employed to identify genes involved in immune evasion.
  • Hepatocyte-specific Stk40 deletion was performed in hydrodynamic plasmid-driven HCC models.
  • The molecular mechanisms of STK40 action were elucidated, including its interaction with COP1 and IFNGR1.
  • Pharmacological inhibition of STK40 using LNP-siRNA was tested in combination with PD-1 blockade.

Main Results:

  • STK40 was identified as a key regulator of immune evasion in HCC.
  • Stk40 ablation synergized with PD-1 blockade, leading to significant tumor regression.
  • Hepatocyte-specific Stk40 deletion abolished HCC development.
  • STK40 promotes IFNGR1 degradation, reducing tumor cell sensitivity to T cell cytotoxicity.
  • STK40 loss enhances dendritic cell activation and T cell responses.
  • Combined STK40 inhibition and PD-1 blockade showed potent anti-tumor effects in various cancer types.

Conclusions:

  • STK40 is a critical mediator of immune evasion in hepatocellular carcinoma.
  • Targeting STK40 represents a promising dual-action strategy to overcome resistance to anti-tumor immunity.
  • Pharmacological inhibition of STK40 in combination with PD-1 blockade offers a potential therapeutic approach for multiple cancers.
Keywords:
CRISPR screeningSTK40anti-tumor immunityhepatocellular carcinomaimmunotherapy

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