STING activation reshapes the tumor microenvironment leading to tumor regression in osteosarcoma

Young, E. P.; Johnson, C. A.; Lee, A. G.; Morris, D.; Tsui, J.; Breese, M. R.; Camara Serrano, J. A.; Schott, C. R.; Abram, C. L.; Leung, S. G.; Sayles, L. C.; Pettiwala, A. M.; Gutierrez Vera, V. S.; Lowell, C. A.; Combes, A. J.; McEachron, T. A.; Sweet-Cordero, E. A.

doi:10.1101/2025.10.24.684275

bioRxiv · 10.1101/2025.10.24.684275

STING activation reshapes the tumor microenvironment leading to tumor regression in osteosarcoma

Young, E. P.·Johnson, C. A.·Lee, A. G.·Morris, D.·Tsui, J.·Breese, M. R.·Camara Serrano, J. A.·Schott, C. R.·Abram, C. L.·Leung, S. G.·Sayles, L. C.·Pettiwala, A. M.·Gutierrez Vera, V. S.·Lowell, C. A.·Combes, A. J.·McEachron, T. A.·Sweet-Cordero, E. A.

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Abstract

Osteosarcomas are characterized by a high degree of aneuploidy, chromothripsis and micronuclei, yet these tumors typically have an immunosuppressive, macrophage-rich, T-cell depleted tumor microenvironment. cGAS-STING dysregulation is a possible mechanism by which immune activation in response to tumor genomic instability could be repressed. We identified almost universal repression of cGAS or STING in human osteosarcomas. However, a STING-activation gene signature was predictive of survival in osteosarcoma patients suggesting potential for activation of this pathway in the osteosarcoma tumor microenvironment. Indeed, in immunocompetent osteosarcoma models, systemic STING agonism led to complete regression and induced lasting immunologic memory. Host STING activation is sufficient to promote this anti-tumor immunity even in the absence of tumor STING. These results nominate the cGAS-STING pathway as an important therapeutic target in osteosarcoma, a disease in which no new curative therapies have been developed in the last 40 years. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/684275v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@15b1e5corg.highwire.dtl.DTLVardef@12650aaorg.highwire.dtl.DTLVardef@79ef71org.highwire.dtl.DTLVardef@15704c9_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Young, E. P., Johnson, C. A., Lee, A. G., Morris, D., Tsui, J., Breese, M. R., Camara Serrano, J. A., Schott, C. R., Abram, C. L., Leung, S. G., Sayles, L. C., Pettiwala, A. M., Gutierrez Vera, V. S., Lowell, C. A., Combes, A. J., McEachron, T. A., Sweet-Cordero, E. A.. 2025-10-25. STING activation reshapes the tumor microenvironment leading to tumor regression in osteosarcoma. https://doi.org/10.1101/2025.10.24.684275

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