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EP277/#794  Sting inhibitors reverse platinum resistance in ovarian cancer by inhibiting the cGAS-sting pathway in cancer-associated fibroblasts
  1. Qing Zhang1,
  2. Jiale Liu1,
  3. Yana Ma2 and
  4. Kun Song1
  1. 1Qilu hospital of Shandong University, Obstetrics and Gynecology, Jinan, Shandong province, China
  2. 2Qilu Hospital of Shandong University, Obstetrics and Gynecology, Jinan, China


Introduction Chemoresistance is a key factor limiting the cure rate of ovarian cancer. Cancer-associated fibroblasts (CAFs) have been shown to be actively involved in cancer progression and chemoresistance. Intratumoral inflammatory environments affect many therapeutic responses, but the underlying mechanisms by which CAF participates in chemoresistance by modulating the tumor’s inflammatory environment are largely unknown.

Methods We cultured primary ovarian cancer-associated fibroblasts, using indirect co-culture to study how ovarian cancer cells activate CAF to participate in ovarian cancer platinum-resistant. WB shows activation of the cGAS-STING pathway in CAF, and IHC shows differential expression of STING in cisplatin-sensitive/resistant patients. Cell viability or apoptosis using CCK8 or apoptosis kits, respectively. The STING antagonist H-151 and the STING agonist MSA-2 investigated the contribution of the cGAS-STING pathway to the chemoresistance of ovarian cancer.

Results After treatment with cisplatin for ovarian cancer cells, the supernatant was indirectly co-cultured with CAFs, and mRNA sequencing showed that the cGAS-STING-IFNB1 pathway was activated in CAFs. We found that IFNB1 can promote platinum resistance in cancer cells by inhibiting cisplatin-induced DNA damage and promoting HRR. Anti-IFNB1 restores platinum sensitivity. In addition, the expression of STING in the tumor stroma is associated with poor prognosis in patients. In vivo experiments showed that inhibition of STING expression could restore platinum sensitivity, while activating STING could not significantly enhance immune killing ability.

Conclusion/Implications Our study shows that activation of the cGAS-STING pathway in CAFs is involved in platinum resistance in ovarian cancer, and STING inhibitors are able to restore ovarian cancer chemotherapy sensitivity.

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