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Epigenetically suppressed tumor cell intrinsic STING promotes tumor immune escape

Hui Zheng1, Lizhen Wu2, Qian Xiao3

  • 1Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|November 27, 2022
PubMed

Insights

KDM5 inhibitors restore STING expression in colon cancer cells, suppressing tumor growth. This research reveals KDM5 inhibitors as potential immune modulators for cancer therapy by reactivating the cGAS-STING pathway.

Area of Science:

  • Immunology
  • Cancer Biology
  • Epigenetics

Background:

  • The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is crucial for cancer immunosurveillance.
  • Pharmaceutical activation of STING shows promise for anti-tumor immunity but faces clinical limitations.
  • Epigenetic silencing of STING in tumors, including colon cancer, contributes to immune escape.

Purpose of the Study:

  • To investigate the role of STING in colorectal cancer growth.
  • To evaluate the efficacy of KDM5 inhibitors in restoring STING expression and function in colon cancer models.
  • To explore KDM5 inhibitors as novel cancer therapeutics.

Main Methods:

  • Utilized MC38 and CT26 syngeneic mouse colorectal cancer models.
  • Assessed the impact of STING loss on tumor progression.
  • Administered KDM5 inhibitors to evaluate their effect on STING expression and tumor growth in immune-competent mice.

Main Results:

  • Loss of STING in tumor cells accelerated colorectal cancer growth.
  • KDM5 inhibitors successfully reactivated STING expression in mouse colon cancer cells.
  • KDM5 inhibitors suppressed colon cancer growth in a STING-dependent manner in vivo.

Conclusions:

  • STING plays a critical role in suppressing colon cancer progression.
  • KDM5 inhibitors can overcome STING silencing, thereby enhancing anti-tumor immunity.
  • KDM5 inhibitors represent a promising new class of immune modulators for cancer treatment.
Keywords:
Cancer ImmunologyCancer epigeneticsHistone demethylaseKDM5STING

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