Coagulation proteases modulate nucleic-acid uptake and cGAS-STING-IFN induction in the tumor microenvironment

Petra Wilgenbus; Jennifer Pott; Sven Pagel; Claudius Witzler; Jennifer Royce; Federico Marini; Sabine Reyda; Thati Madhusudhan; Thomas Kindler; Anne Hausen; Matthias M. Gaida; Hartmut Weiler; Wolfram Ruf; Claudine Graf

doi:10.1172/jci.insight.190311

Coagulation proteases modulate nucleic-acid uptake and cGAS-STING-IFN induction in the tumor microenvironment

Petra Wilgenbus,¹ Jennifer Pott,¹ Sven Pagel,¹ Claudius Witzler,¹ Jennifer Royce,² Federico Marini,³ Sabine Reyda,¹ Thati Madhusudhan,¹ Thomas Kindler,⁴ Anne Hausen,⁵ Matthias M. Gaida,⁶ Hartmut Weiler,⁷ Wolfram Ruf,¹ and Claudine Graf¹

Published July 22, 2025 - More info

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Abstract

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 anti-tumor responses. These data provide mechanistic insights into the emerging clinical evidence demonstrating the translational potential of FXa inhibition to synergize with immunotherapy.

Coagulation proteases modulate nucleic-acid uptake and cGAS-STING-IFN induction in the tumor microenvironment

Petra Wilgenbus,¹ Jennifer Pott,¹ Sven Pagel,¹ Claudius Witzler,¹ Jennifer Royce,² Federico Marini,³ Sabine Reyda,¹ Thati Madhusudhan,¹ Thomas Kindler,⁴ Anne Hausen,⁵ Matthias M. Gaida,⁶ Hartmut Weiler,⁷ Wolfram Ruf,¹ and Claudine Graf¹

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Coagulation proteases modulate nucleic-acid uptake and cGAS-STING-IFN induction in the tumor microenvironment

Petra Wilgenbus,1 Jennifer Pott,1 Sven Pagel,1 Claudius Witzler,1 Jennifer Royce,2 Federico Marini,3 Sabine Reyda,1 Thati Madhusudhan,1 Thomas Kindler,4 Anne Hausen,5 Matthias M. Gaida,6 Hartmut Weiler,7 Wolfram Ruf,1 and Claudine Graf1

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Petra Wilgenbus,¹ Jennifer Pott,¹ Sven Pagel,¹ Claudius Witzler,¹ Jennifer Royce,² Federico Marini,³ Sabine Reyda,¹ Thati Madhusudhan,¹ Thomas Kindler,⁴ Anne Hausen,⁵ Matthias M. Gaida,⁶ Hartmut Weiler,⁷ Wolfram Ruf,¹ and Claudine Graf¹