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 a 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 demonstrate that the expression of the transcription factor OCT4 is upregulated in persistent cells that survive treatment with trabectedin and olaparib, 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. These molecular events enhance the antitumor efficacy of immunotherapy with NK and CIK cells, targeting both the bulk population and residual drug-tolerant cells. In conclusion, the activation of the cGAS-STING pathway has a double-edged effect, enriching the OCT4<sup>+</sup> persistent cell population while increasing the expression of NK/CIK ligands. The addition of olaparib to trabectedin potentiates the cGAS-STING pathway activation and the upregulation of NKG2DLs, while simultaneously counteracting the OCT4 overexpression. Therefore, sequential treatment with trabectedin and olaparib followed by NK/CIK immunotherapy represents a promising strategy against advanced sarcomas and warrants further investigation.
Authors
- G Giordano (ORCID: https://orcid.org/0000-0003-0177-4430)
- Chiara Riganti (ORCID: https://orcid.org/0000-0001-9787-4836)
- Giulia Mesiano
- Michele De Bortoli (ORCID: https://orcid.org/0000-0002-6666-9052)
- Federica Capozzi (ORCID: https://orcid.org/0000-0002-6458-5699)
- Alessandra Merlini (ORCID: https://orcid.org/0000-0002-5280-1411)
- Silvia Brusco
- Federica Galvagno (ORCID: https://orcid.org/0000-0003-2245-6810)
- Dario Sangiolo (ORCID: https://orcid.org/0000-0002-7163-7071)
- Giovanni Grignani (ORCID: https://orcid.org/0000-0001-5515-569X)
- Lorenzo D’Ambrosio (ORCID: https://orcid.org/0000-0003-3294-8819)
- Ymera Pignochino (ORCID: https://orcid.org/0000-0001-5073-8618)
- Santina Cutrupi (ORCID: https://orcid.org/0000-0002-2358-5852)
- Annamaria Massa (ORCID: https://orcid.org/0000-0002-8156-3037)
- Valeria Leuci (ORCID: https://orcid.org/0000-0003-3592-9779)
- Giulio Ferrero (ORCID: https://orcid.org/0000-0002-4580-0680)
- Cristina Tucciarello
- Elisabetta Liuzzi (ORCID: https://orcid.org/0009-0000-7369-1832)
- Simona Comparato
- Shahab Majidi
Institutions
- Politecnico di Torino (IT)
- Italian institute for Genomic Medicine (IT)
- Princess Máxima Center (NL)
- Candiolo Cancer Institute (IT)
- Ospedale San Luigi Gonzaga (IT)
- University of Turin (IT)
Publication Details
- Journal
- Cancer Immunology Immunotherapy
- Published
- 2025-09-23
- DOI
- https://doi.org/10.1007/s00262-025-04141-w
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Ministero della Salute
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- PharmaMar
- Alleanza Contro il Cancro