The cGAS-STING pathway is a master regulator of OCT4 expression in persistent sarcoma cells and enhances cellular immunotherapy with NK and CIK lymphocytes

Advanced sarcomas have poor prognosis and limited therapeutic options. Disease recurrence is caused by persistent cells that survive drug treatments. The alkylating agent trabectedin, when combined with the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor olaparib, exhibits variable antitumor effects in advanced sarcomas. In this study, we demonstrated that the expression of the transcription factor OCT4 is upregulated in persistent cells surviving trabectedin and olaparib treatment through the cGAS-STING-IRF3-IFNβ pathway. This route also leads to the upregulation of natural killer (NK) and cytokine-induced killer (CIK) lymphocyte activating ligands. This upregulation promoted the antitumor effect of immunotherapy with NK and CIK cells against both bulk and persistent cells that survive drug treatment. In conclusion, activation of the cGAS-STING pathway due to trabectedin + olaparib treatment has a double-edged sword effect, enriching the OCT4 ⁺ persistent cell population while increasing the expression of NK/CIK ligands. Therefore, sequential treatment with trabectedin and olaparib followed by NK/CIK immunotherapy is a promising strategy against advanced sarcomas and deserves further investigation.