GSDME介导的焦亡调节肺腺癌的免疫抑制微环境，这一成果由天津医科大学陈军小组经过不懈努力而取得。这一研究成果发表在2026年3月3日出版的国际学术期刊《中国药理学报》上。

该研究团队的目的是建立一个与焦亡相关的预后模型，并阐明GSDME介导的焦亡在LUAD中形成肿瘤免疫的复杂动力学。研究组开发了一个以机器学习为主题的与焦热相关的预测模型。CHX和TNF-α诱导GSDME介导的LUAD细胞焦亡。采用酶联免疫吸附法测定细胞焦亡后上清液和PD-1/PD-L1抗体治疗前患者血清中HMGB1的含量。

在体内，Lewis肺癌（LLC）的C57小鼠接受顺铂和/或caspase-3抑制剂、抗PD-1和IL-8抑制剂治疗，并监测肿瘤生长。他们的预后预测模型（PYR_score），建立在热分解相关基因上，在预测LUAD预后的不同数据集上显示出很高的有效性。机器学习分析显示，较高的PYR_score值与较短的无进展和总生存期相关。CHX和TNF-α诱导GSDME介导的焦亡，HMGB1升高。HMGB1升高与LUAD患者免疫检查点抑制剂治疗效果较差相关。HMGB1可提高Treg细胞体外增殖能力和IL-8分泌。Caspase-3和IL-8抑制剂减缓了肿瘤生长，IL-8抑制剂可能增强了肝癌小鼠抗PD-1免疫治疗的有效性。

总之，他们的新PYR_score是一个机器人预后标记，提供跨不同数据集的预测能力。GSDME介导的焦亡通过HMGB1、Treg细胞和MDSCs的升高来调节免疫抑制微环境。IL-8抑制剂可能抑制Treg和MDSCs，增强抗PD-1免疫治疗的有效性。进一步的临床验证和探索针对这些途径的治疗干预对于将这些发现转化为临床实践至关重要。

据悉，尽管越来越多的人认识到焦亡，特别是与GSDME有关的焦亡，但其对肿瘤预后和免疫微环境的确切影响仍不清楚，需要在肺腺癌（LUAD）的背景下进行全面的研究。

附：英文原文

Title: GSDME-mediated pyroptosis modulates the immunosuppressive microenvironment in lung adenocarcinoma

Author: Zhu, Guang-sheng, Li, Xuan-guang, Cao, Pei-jun, Wang, Ya-nan, Wang, Ying-jie, Zhang, Zi-he, Li, Bo-shi, Chen, Pei-jie, Li, Yong-wen, Chen, Chen, Zhang, Hong-bing, Liu, Hong-yu, Chen, Jun

Issue&Volume: 2026-03-03

Abstract: Despite the increasing recognition of pyroptosis, particularly that involving GSDME, its precise impact on tumor prognosis and the immune microenvironment remains elusive, necessitating a comprehensive investigation in the context of lung adenocarcinoma (LUAD). We aimed to construct a pyroptosis-related prognostic model and to elucidate the intricate dynamics of GSDME-mediated pyroptosis in shaping tumor immunity in LUAD. We developed a pyroptosis-related prognostic model using machine learning. GSDME-mediated pyroptosis in LUAD cells was induced using CHX and TNF-α. HMGB1 content in the cell supernatant after cell pyroptosis and in serum from patients before treatment with PD-1/PD-L1 antibodies was determined by Enzyme-Linked Immunosorbent Assay. In vivo, Lewis lung carcinoma (LLC)-bearing C57 mice were treated with cisplatin and/or caspase-3 inhibitors, anti-PD-1, and IL-8 inhibitors, with tumor growth monitored. Our prognostic prediction model (PYR_score), built upon pyroptosis-related genes, demonstrated high efficacy in predicting LUAD prognosis across diverse datasets. Machine learning analyses revealed that higher PYR_score values correlated with shorter progression-free and overall survival. CHX and TNF-α induced GSDME-mediated pyroptosis with elevated HMGB1. Increased HMGB1 was associated with worse therapeutic efficacy of immune checkpoint inhibitors in LUAD patients. HMGB1 increased the proliferative ability and IL-8 secretion of Treg cells in vitro. Caspase-3 and IL-8 inhibitors slowed tumor growth, and IL-8 inhibitors possibly enhanced the effectiveness of anti-PD-1 immunotherapy in LLC-bearing mice. In summary, our novel PYR_score is a robust prognostic marker, offering predictive power across different datasets. GSDME-mediated pyroptosis modulated the immunosuppressive microenvironment via elevations in HMGB1, Treg cells, and MDSCs. IL-8 inhibitors may inhibit Tregs and MDSCs and enhance the effectiveness of anti-PD-1 immunotherapy. Further clinical validation and exploration of therapeutic interventions targeting these pathways are essential for translating these findings into clinical practice.

DOI: 10.1038/s41401-026-01771-3

Source: https://www.nature.com/articles/s41401-026-01771-3