During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1β after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1β addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC.
过去十年间，酪氨酸激酶抑制剂（TKIs）索拉非尼与瑞戈非尼已成为晚期肝细胞癌（HCC）的标准全身治疗方案。既往研究提示索拉非尼可激活炎症小体通路，但该通路在索拉非尼与瑞戈非尼信号传导中的作用尚未在肝癌患者中得到阐明。为此，我们在小鼠HCC模型中分析了炎症小体相关的转录组学变化。实验数据证实两种TKI治疗后均出现炎症小体激活，且呈现相似的基因表达上调模式。基于人类数据库分析结果，炎症小体基因的转录水平升高与男性肝癌患者不良预后相关，提示炎症小体激活在HCC治疗中可能存在性别依赖性效应。在肝癌组织及癌旁组织活检样本中，我们观察到男性患者经索拉非尼或瑞戈非尼治疗后，炎症小体激活模式呈现持续性增强。通过实验性HCC模型进一步验证发现，炎症小体抑制剂（MCC950）可增强索拉非尼的抗癌活性，但在HCC细胞系中未观察到直接体外效应，这为炎症小体参与索拉非尼作用机制提供了佐证。此外，激活的人THP-1巨噬细胞在索拉非尼给药后释放IL-1β，而添加IL-1β的3D Hep3B球体模型显示肿瘤生长加速，表明肝脏微环境在炎症小体作用机制中发挥关键作用。综上所述，本研究首次揭示炎症小体通路可作为索拉非尼或瑞戈非尼治疗的潜在作用靶点，并证实肝癌及癌旁组织中炎症小体特征性变化与TKI给药相关。因此，靶向抑制炎症小体激活（尤其针对男性患者）可能有助于克服索拉非尼或瑞戈非尼耐药性，提升TKI类药物治疗HCC的临床疗效。
肿瘤(癌症)患者之家