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mTORC2 inhibition reduces tumor burden via STAT1 activation and enhanced response to anti–PD-L1 therapy
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mTORC2 inhibition reduces tumor burden via STAT1 activation and enhanced response to anti–PD-L1 therapy
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Journal Article
mTORC2 inhibition reduces tumor burden via STAT1 activation and enhanced response to anti–PD-L1 therapy
2025
Overview
Although melanoma treatment has progressed considerably in recent years, increasing patient response rates remains a significant challenge. The interferon pathway is known to promote immune recognition, but its sustained activation can contribute to adaptive immune exhaustion. In this study, we demonstrate that myeloid-specific deletion of Rictor in a mouse melanoma model enhances STAT1 signaling while reducing PD-L1 expression. Furthermore, IFN-γ–activated macrophages inhibited melanoma growth in a human skin organoid model. Notably, in vivo inhibition of AKT, in conjunction with anti–PD-L1 therapy, suppressed tumor progression. Mechanistically, we identified IFN-γ–mediated downregulation of IGF-1 as a key event during inflammation, and showed that supplementation with recombinant IGF-1 dampens STAT1 activation. Our findings reveal that targeting the Rictor-AKT axis induces a dual effect - boosting pro-inflammatory signaling while downregulating immunosuppressive factors such as PD-L1 and IGF-1. These results support the potential of AKT inhibitors to enhance the efficacy of immune checkpoint therapies in melanoma patients.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/31
/ 13/51
/ 13/95
/ 14/1
/ 14/19
/ 64/60
/ Animals
/ B7-H1 Antigen - antagonists & inhibitors
/ Biomedical and Life Sciences
/ Humans
/ Immune Checkpoint Inhibitors - pharmacology
/ Immune Checkpoint Inhibitors - therapeutic use
/ Insulin-like growth factor I
/ Insulin-Like Growth Factor I - metabolism
/ Interferon-gamma - metabolism
/ Interferon-gamma - pharmacology
/ Mechanistic Target of Rapamycin Complex 2 - antagonists & inhibitors
/ Mechanistic Target of Rapamycin Complex 2 - metabolism
/ Melanoma
/ Melanoma, Experimental - drug therapy
/ Melanoma, Experimental - pathology
/ Mice
/ Proteins
/ Proto-Oncogene Proteins c-akt - metabolism
/ Signal Transduction - drug effects
/ STAT1 Transcription Factor - metabolism
/ Tumors
