PXD062987

PXD062987 is an original dataset announced via ProteomeXchange.

Title	Inhibition of TBK1/IKKe mediated RIPK1 phosphorylation sensitizes tumors to immune cell killing.
Description	Resistance to immune cell-mediated cytotoxicity poses a significant challenge in cancer therapy, compromising the efficacy of immunotherapeutic approaches such as immune checkpoint blockade (ICB) treatment. To enhance therapy outcomes, it is crucial to identify interventions that can synergize with ICB therapy to overcome tumor resistance. Therefore, we need to define the cellular mechanisms that sensitize tumors to cytotoxic T cells. CD8 T cells rely on cytokines such as TNF to carry out their cytotoxicity against tumors, and recent findings link select tumor mutations in the TNF pathway to increased T cell killing, in a manner dependent on RIPK1 kinase. Here, we demonstrate that sensitized tumor cells fail to initiate inhibitory RIPK1 phosphorylation at site S25 upon T cell attack, thereby foregoing a pro-survival checkpoint early in TNF signal transduction. Consequently, tumor cells experiencing a loss of TNF-induced RIPK1 S25 phosphorylation exhibit increased RIPK1 activation and fail to recruit non-canonical IKK kinases (TBK1 and IKKe) to the TNFR1 complex. Functional knockouts of TBK1 and IKKe in melanoma cells result in heightened sensitivity not only in CD8 T cell but also in Natural Killer cell attacks. Our findings indicate that preventing TBK1 and IKKe recruitment to the TNF signaling complex, thereby blocking RIPK1 pro-survival phosphorylation and promoting direct RIPK1 activation, is a tractable strategy to increase tumor sensitivity to immune cell killing and has the potential to benefit current immunotherapy interventions.
HostingRepository	PRIDE
AnnounceDate	2025-12-08
AnnouncementXML	Submission_2025-12-07_18:01:15.358.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kelly Stecker
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF; Orbitrap Exploris 480; TSQ Altis

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-15 08:10:44	ID requested
⏵ 1	2025-12-07 18:01:16	announced

Piskopou A, Vredevoogd DW, Kong X, Peeper DS, Altelaar M, Stecker KE, mediated RIPK1 phosphorylation sensitizes tumors to immune cell killing. Cell Death Discov, 11(1):551(2025) [pubmed]

10.1038/s41420-025-02841-x;

submitter keyword: Biotin AP,Phosphorylation, tumors, TNF signaling, TBK1, RIPK1

Stecker Group
contact affiliation	Biomolecular Mass Spectrometry and Proteomics, Utrecht University
contact email	k.e.stecker@uu.nl
lab head
Kelly Stecker
contact affiliation	Utrecht University
contact email	k.e.stecker@uu.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD062987
     1. Label: PRIDE project
     2. Name: Inhibition of TBK1/IKKe mediated RIPK1 phosphorylation sensitizes tumors to immune cell killing.