Immune evasion in the tumor microenvironment (TME) is a crucial barrier for effective cancer therapy, and plasticity of innate immune cells may contribute to failures of targeted immunotherapies. Here, we show that rivaroxaban, a direct inhibitor of activated coagulation factor X (FX), promotes antitumor immunity by enhancing infiltration of dendritic cells and cytotoxic T cells at the tumor site. Profiling FX expression in the TME identifies monocytes and macrophages as crucial sources of extravascular FX. By generating mice with immune cells lacking the ability to produce FX, we show that myeloid cell–derived FX plays a pivotal role in promoting tumor immune evasion. In mouse models of cancer, we report that the efficacy of rivaroxaban is comparable with anti–programmed cell death ligand 1 (PD-L1) therapy and that rivaroxaban synergizes with anti–PD-L1 in improving antitumor immunity. Mechanistically, we demonstrate that FXa promotes immune evasion by signaling through protease-activated receptor 2 and that rivaroxaban specifically targets this cell-autonomous signaling pathway to reprogram tumor-associated macrophages. Collectively, our results have uncovered the importance of FX produced in the TME as a regulator of immune cell activation and suggest translational potential of direct oral anticoagulants to remove persisting roadblocks for immunotherapy and provide extravascular benefits in other diseases.

肿瘤微环境（TME）中的免疫逃逸是有效癌症治疗的关键障碍，而先天免疫细胞的可塑性可能会导致靶向免疫疗法的失败。在这里，我们显示利伐沙班是活化凝血因子X（FX）的直接抑制剂，可通过增强树突状细胞和细胞毒性T细胞在肿瘤部位的浸润来促进抗肿瘤免疫力。在TME中对FX表达进行分析可将单核细胞和巨噬细胞识别为血管外FX的重要来源。通过用缺乏产生FX的能力的免疫细胞生成小鼠，我们证明了髓样细胞衍生的FX在促进肿瘤免疫逃逸中起关键作用。在癌症的小鼠模型中 我们报告说，利伐沙班的疗效与抗程序性细胞死亡配体1（PD-L1）治疗相当，并且利伐沙班与抗PD-L1协同提高抗肿瘤免疫力。从机制上讲，我们证明FXa可以通过蛋白酶激活的受体2信号传导来促进免疫逃逸，并且利伐沙班特异地靶向这种细胞自主的信号通路来重新编程与肿瘤相关的巨噬细胞。总的来说，我们的结果揭示了TME中产生的FX作为免疫细胞活化调节剂的重要性，并暗示了直接口服抗凝剂的翻译潜力，可以消除持久性免疫疗法的障碍，并在其他疾病中提供血管外益处。我们证明FXa通过蛋白酶激活受体2的信号传导促进免疫逃逸，并且利伐沙班特异地靶向这种细胞自主的信号通路来重新编程与肿瘤相关的巨噬细胞。总的来说，我们的结果揭示了TME中产生的FX作为免疫细胞活化调节剂的重要性，并暗示了直接口服抗凝剂的翻译潜力，可以消除持久性免疫疗法的障碍，并在其他疾病中提供血管外益处。我们证明FXa通过蛋白酶激活受体2的信号传导来促进免疫逃逸，并且利伐沙班特异地靶向这种细胞自主的信号通路来重新编程与肿瘤相关的巨噬细胞。总的来说，我们的结果揭示了TME中产生的FX作为免疫细胞活化调节剂的重要性，并暗示了直接口服抗凝剂的翻译潜力，可以消除持久性免疫疗法的障碍，并在其他疾病中提供血管外益处。