NADPH oxidases catalyze the production of reactive oxygen species and are involved in physio/pathological processes. NOX1 is highly expressed in colon cancer and promotes tumor growth. To investigate the efficacy of NOX1 inhibition as an anticancer strategy, tumors were grown in immunocompetent, immunodeficient, or NOX1-deficient mice and treated with the novel NOX1-selective inhibitor GKT771. GKT771 reduced tumor growth, lymph/angiogenesis, recruited proinflammatory macrophages, and natural killer T lymphocytes to the tumor microenvironment. GKT771 treatment was ineffective in immunodeficient mice bearing tumors regardless of their NOX-expressing status. Genetic ablation of host NOX1 also suppressed tumor growth. Combined treatment with the checkpoint inhibitor anti-PD1 antibody had a greater inhibitory effect on colon carcinoma growth than each compound alone. In conclusion, GKT771 suppressed tumor growth by inhibiting angiogenesis and enhancing the recruitment of immune cells. The antitumor activity of GKT771 requires an intact immune system and enhances anti-PD1 antibody activity. Based on these results, we propose blocking of NOX1 by GKT771 as a potential novel therapeutic strategy to treat colorectal cancer, particularly in combination with checkpoint inhibition.

中文翻译：

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抑制宿主NOX1可阻止肿瘤生长，并增强基于检查点抑制剂的免疫疗法。

NADPH氧化酶催化活性氧的产生，并参与生理/病理过程。NOX1在结肠癌中高表达并促进肿瘤生长。为了研究NOX1抑制作为一种抗癌策略的功效，使肿瘤在具有免疫能力，免疫缺陷或NOX1缺陷的小鼠中生长，并用新型NOX1选择性抑制剂GKT771治疗。GKT771减少了肿瘤微环境的肿瘤生长，淋巴/血管生成，募集的促炎巨噬细胞和天然杀伤性T淋巴细胞。不论其表达NOX的状态如何，GKT771治疗对带有肿瘤的免疫缺陷小鼠均无效。宿主NOX1的遗传消融也抑制了肿瘤的生长。与检查点抑制剂抗PD1抗体联合治疗比单独使用每种化合物对结肠癌的生长具有更大的抑制作用。总之，GKT771通过抑制血管生成和增强免疫细胞的募集来抑制肿瘤的生长。GKT771的抗肿瘤活性需要完整的免疫系统并增强抗PD1抗体的活性。基于这些结果，我们建议通过GKT771阻断NOX1作为治疗结直肠癌的潜在新疗法，特别是与检查点抑制结合使用。