瑞戈非尼是一种口服多激酶抑制剂，被批准用于治疗各种转移性/晚期癌症。尽管临床试验已报道瑞戈非尼对多种癌症类型的疗效，但其对头颈鳞状细胞癌（HNSCC）的免疫调节活性仍不清楚。本研究通过使用两种头颈鳞状细胞癌小鼠模型研究了瑞戈非尼对肿瘤发生的影响。通过流式细胞术、RNA 测序和多重免疫荧光染色评估肿瘤组织中免疫细胞的分布。瑞戈非尼在我们的 HNSCC 小鼠模型中表现出显着的抗肿瘤活性。肿瘤浸润淋巴细胞分离和RNA测序表明瑞戈非尼可以激活免疫功能。此外，瑞戈非尼处理的肿瘤条件培养基可调节离体巨噬细胞增殖。我们的数据表明瑞戈非尼通过调节肿瘤和免疫细胞来调节免疫功能。具体来说，瑞戈非尼通过抑制巨噬细胞调节剂纤溶酶原激活剂抑制剂 1 (PAI-1) 的产生，诱导巨噬细胞向促炎 M1 表型极化。此外，瑞戈非尼抑制离体人 HNSCC 类器官分泌 PAI-1。瑞戈非尼增强 M1/M2 巨噬细胞极化并抑制癌细胞分泌 PAI-1，导致 HNSCC 肿瘤微环境中巨噬细胞从 M2 向 M1 转变。版权所有 © 2024。由爱思唯尔公司出版。

Regorafenib, an oral multikinase inhibitor, is approved for the treatment of various metastatic/advanced cancers. Although clinical trials have reported the efficacy of regorafenib in multiple cancer types, its immunomodulatory activity in head and neck squamous cell carcinoma (HNSCC) remains unclear.This study investigated the effects of regorafenib on tumorigenesis by using two mouse models of HNSCC. The distribution of immune cells in tumor tissues was assessed through flow cytometry, RNA sequencing, and multiplex immunofluorescence staining.Regorafenib exhibited significant antitumor activity in our HNSCC mouse models. Tumor-infiltrating lymphocyte isolation and RNA sequencing revealed that regorafenib can activate immune functions. Moreover, regorafenib-treated tumor-conditioned medium regulated macrophage proliferation ex vivo. Our data suggests that regorafenib modulates immune function by regulating both tumor and immune cells. Specifically, regorafenib induced the polarization of macrophages toward the proinflammatory M1 phenotype by suppressing the production of plasminogen activator inhibitor 1 (PAI-1), a macrophage regulator. In addition, regorafenib suppressed the secretion of PAI-1 from ex vivo human HNSCC organoids.Regorafenib enhances M1/M2 macrophage polarization and suppresses PAI-1 secretion from cancer cells, leading to a shift from M2 to M1 macrophages in the HNSCC tumor microenvironment.Copyright © 2024. Published by Elsevier Inc.