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Comment
. 2023 Jul 17;8(1):272.
doi: 10.1038/s41392-023-01530-4.

Neutrophil-sourced TNF in cancer: deciphering an intricate orchestrator of immunosuppressive communication in the tumor microenvironment

Xinyuan Zhao #  1 , Ye Lu #  1 , Li Cui  2   3
Affiliations
Comment

Neutrophil-sourced TNF in cancer: deciphering an intricate orchestrator of immunosuppressive communication in the tumor microenvironment

Xinyuan Zhao et al. Signal Transduct Target Ther. .
No abstract available

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Cell-autonomous Cxcl1 orchestrates T-cell restriction through CXCR2-expressing PMN-MDSC interaction and PMN-MDSC-derived TNF-driven stromal inflammation, immune tolerance, and therapeutic resistance in PDAC. Co-alterations of KRAS-TP53 transcriptionally enhance CXCL1 expression via a CREB-dependent mechanism in PDAC cells, facilitating tumor cell interaction with CXCR2+ PMN-MDSCs, which in turn activates the CXCR2-MAPK-TNF signaling cascade in PMN-MDSCs. Neutrophil-derived TNF exacerbates Treg dysfunction in PDAC through transmembrane TNF-TNFR2 signaling, ultimately leading to the suppression of CD8+ T-cell activity and hindering the immune response. Concurrently, transmembrane TNF-TNFR2 interactions substantially increase the iCAF:myCAF ratio and amplify IL-6/STAT3 signaling in the tumor, promoting stromal inflammation and therapeutic resistance. Notably, PMN-MDSCs significantly elevate Cxcl1 expression in both PDAC cells and CAFs. Targeting TNFR2 disrupts this intricate network, enhancing chemotherapy sensitivity in vivo. Created with BioRender.com
See this image and copyright information in PMC

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