TY  - JOUR
AU  - Wilgenbus, Petra
AU  - Pott, Jennifer
AU  - Pagel, Sven
AU  - Witzler, Claudius
AU  - Royce, Jennifer
AU  - Marini, Federico
AU  - Reyda, Sabine
AU  - Madhusudhan, Thati
AU  - Kindler, Thomas
AU  - Hausen, Anne
AU  - Gaida, Matthias M
AU  - Weiler, Hartmut
AU  - Ruf, Wolfram
AU  - Graf, Claudine
TI  - Coagulation proteases modulate nucleic acid uptake and cGAS-STING-IFN induction in the tumor microenvironment.
JO  - JCI insight
VL  - 10
IS  - 17
SN  - 2379-3708
CY  - Ann Arbor, Michigan
PB  - JCI Insight
M1  - DKFZ-2025-01876
SP  - e190311
PY  - 2025
AB  - Malignancies increase the risk for thrombosis and metastasis dependent on complex interactions of innate immune cells, platelets, and the coagulation system. Immunosuppressive functions of platelets and macrophage-derived coagulation factors in the tumor microenvironment (TME) drive tumor growth. Here, we show that patients with malignancies and tumor-bearing mice have increased levels of coagulation factor (F) X-expressing circulating monocytes engaged in platelet aggregate formation. This interaction and resulting thrombin generation on platelets interferes with monocyte differentiation and antigen uptake of antigen-presenting cells (APCs). Myeloid cell-specific deletion of FX or abrogated FXa signaling via protease activated receptor 2 (PAR2) averts the suppressive activity of platelets on tumor cell debris uptake and promotes the immune stimulatory activity of APCs in the TME. Myeloid cell FXa-PAR2 signaling deficiency specifically enhances activation of the cGAS-STING-IFN-I pathway with a resulting expansion of antigen experienced progenitor exhausted CD8+ T cells. Pharmacological blockade of FXa with direct oral anticoagulants expands T cell priming-competent immune cells in the TME and synergizes with the reactivation of exhausted CD8+ T cells by immune checkpoint inhibitors for improved antitumor responses. These data provide mechanistic insights into the emerging clinical evidence demonstrating the translational potential of FXa inhibition to synergize with immunotherapy.
KW  - Tumor Microenvironment: immunology
KW  - Animals
KW  - Humans
KW  - Mice
KW  - Membrane Proteins: metabolism
KW  - Nucleotidyltransferases: metabolism
KW  - Neoplasms: immunology
KW  - Neoplasms: pathology
KW  - Signal Transduction
KW  - Blood Platelets: metabolism
KW  - Blood Platelets: immunology
KW  - Factor Xa: metabolism
KW  - Factor Xa: genetics
KW  - Female
KW  - Receptor, PAR-2: metabolism
KW  - Receptor, PAR-2: genetics
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - Mice, Inbred C57BL
KW  - Monocytes: metabolism
KW  - Monocytes: immunology
KW  - Antigen-Presenting Cells: immunology
KW  - Male
KW  - Cancer immunotherapy (Other)
KW  - Coagulation (Other)
KW  - Immunology (Other)
KW  - Oncology (Other)
KW  - Platelets (Other)
KW  - Vascular biology (Other)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Nucleotidyltransferases (NLM Chemicals)
KW  - STING1 protein, human (NLM Chemicals)
KW  - cGAS protein, human (NLM Chemicals)
KW  - Sting1 protein, mouse (NLM Chemicals)
KW  - Factor Xa (NLM Chemicals)
KW  - Receptor, PAR-2 (NLM Chemicals)
KW  - cGAS protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40694429
DO  - DOI:10.1172/jci.insight.190311
UR  - https://inrepo02.dkfz.de/record/304484
ER  -