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目的 探讨瑞戈非尼联合免疫检查点抑制剂（immune checkpoint inhibitor, ICI）治疗经仑伐替尼联合ICI治疗失败的晚期原发性肝癌患者的疗效，及其对肿瘤相关巨噬细胞极化的影响及可能机制。方法 纳入8例经仑伐替尼联合ICI治疗失败后，换用瑞戈非尼联合原ICI治疗的晚期原发性肝癌患者。收集患者换药前及治疗3 d后的外周血，采用流式细胞术检测外周血中M1、M2巨噬细胞比例，ELISA法检测血清中相关细胞因子水平。体外实验采用THP-1来源巨噬细胞，设立溶剂对照组、巨噬细胞集落刺激因子（macrophage colony-stimulating factor, M-CSF）组、瑞戈非尼组、M-CSF+瑞戈非尼共处理组及M-CSF+PLX3397阳性对照组，检测巨噬细胞表型、细胞因子分泌水平及集落刺激因子1受体（colony-stimulating factor 1 receptor, CSF1R）通路相关蛋白磷酸化水平。结果 临床疗效方面，8例患者均未达到客观缓解，疾病控制率为25.0%(2/8)，中位无进展生存期为2.85个月，提示该治疗方案临床获益极为有限。与治疗前相比，治疗后患者外周血M2型巨噬细胞比例显著下降（P=0.016）,M1型巨噬细胞比例呈上升趋势（P=0.078）;M1型巨噬细胞相关促炎因子[诱导型一氧化氮合酶、肿瘤坏死因子（tumor necrosis factor, TNF）-α、白细胞介素（interleukin, IL）-12]水平显著升高，M2巨噬细胞相关免疫抑制因子（精氨酸酶1、TGF-β）水平显著降低（均P<0.01）；血清IL-6水平降低而IL-10水平升高（均P<0.01）。体外实验显示，瑞戈非尼可显著下调M-CSF诱导的p-CSF1R表达（P<0.05），显著上调M1型巨噬细胞标志物CD86表达、下调M2型巨噬细胞标志物CD206表达（均P<0.0001），并显著促进TNF-α分泌、抑制IL-10分泌（均P<0.0001）。结论 经仑伐替尼联合ICI治疗失败的晚期原发性肝癌患者，换用瑞戈非尼联合原ICI治疗，未观察到有意义的临床获益。瑞戈非尼可促进患者外周血巨噬细胞向M1型极化，其机制可能与抑制CSF1R磷酸化有关。本研究为初步机制探索性观察报告，结论需前瞻性大样本研究进一步验证。
Abstract：Objective To investigate the efficacy of regorafenib combined with the original immune checkpoint inhibitor(ICI) in patients with advanced primary liver cancer who were refractory to lenvatinib plus ICI, and its effect on tumor-associated macrophage(TAM) polarization and the underlying mechanisms. Methods Eight patients with advanced primary liver cancer who failed treatment with lenvatinib combined with ICI and subsequently received regorafenib alongside the original ICI were retrospectively included. Peripheral blood was collected before and 3 d after switching to regorafenib. The proportions of M1 and M2 macrophages were measured by flow cytometry, and serum cytokine levels were quantified by ELISA. In vitro experiments were performed on THP-1-derived macrophages under five conditions: solvent control, M-CSF, regorafenib, M-CSF + regorafenib, and M-CSF + PLX3397(positive control). Macrophage phenotype, cytokine secretion, and CSF1R pathway phosphorylation were assessed. Results No patient achieved objective response(ORR=0). The disease control rate(DCR) was 25.0%(2/8), and the median progression-free survival(mPFS) was 2.85 months, indicating very limited clinical benefit. Compared with pre-treatment levels, the proportion of M2 macrophages decreased significantly(P=0.016), while M1 macrophages showed an increasing trend(P=0.078). M1-associated proinflammatory factors(iNOS, TNF-α, IL-12) significantly increased, while M2-associated immunosuppressive factors(Arg1, TGF-β) significantly decreased(P<0.01). Serum IL-6 decreased and IL-10 increased(P<0.01). In vitro, regorafenib significantly downregulated M-CSF-induced p-CSF1R expression(P<0.05), upregulated the M1 marker CD86, downregulated the M2 marker CD206(P<0.0001), promoted TNF-α secretion, and inhibited IL-10 secretion(P<0.0001). Conclusion Switching to regorafenib combined with the original ICI in patients with advanced primary liver cancer who failed lenvatinib plus ICI showed no meaningful clinical benefit. Regorafenib promoted M1 polarization of peripheral macrophages, possibly through inhibition of CSF1R phosphorylation. This study is a preliminary hypothesis-generating observation report, and the conclusions require validation in prospective studies with larger sample sizes.
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基本信息:
中图分类号:R735.7
引用信息:
[1]郏梦蝶,潘仕达,余滢滢,等.瑞戈非尼对仑伐替尼联合免疫检查点抑制剂治疗失败后原发性肝癌患者巨噬细胞极化的影响及机制探索[J].传染病信息,2026,39(03):225-232+237.
基金信息:
国家科技重大专项“新发突发与重大传染病防控国家科技重大专项”（2025ZD01905800）; 国家重点研发计划“病原学与防疫技术体系研究”专项（2024YFC2311101）
2026-06-30
2026-06-30