Xu Chengyuan, Zhang Siqi, Sun Bin, Yu Zicheng, Liu Hailong
Department of General, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China.
Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China.
Front Immunol. 2025 Aug 12;16:1639303. doi: 10.3389/fimmu.2025.1639303. eCollection 2025.
Macrophage polarization plays a pivotal role in shaping the tumor microenvironment and influencing rectal cancer progression. However, the metabolic and prognostic regulators governing this process remain largely undefined.
We constructed a macrophage polarization gene signature (MPGS) by integrating weighted gene co-expression network analysis (WGCNA) with multiple machine learning algorithms across two independent cohorts: 363 rectal cancer samples from GSE87211 and 177 samples from The Cancer Genome Atlas (TCGA). The prognostic performance of MPGS was evaluated across rectal and multiple other cancer types. Functional analyses, single-cell RNA sequencing, immunohistochemistry of clinical specimens, and cellular assays were employed to investigate the role of the MPGS hub gene, , in tumor biology and immune modulation.
The MPGS exhibited robust prognostic capability and effectively predicted responses to immunotherapy and various chemotherapeutic agents. Both MPGS and its central metabolic component, , were closely linked to M2 macrophage infiltration, immunosuppressive tumor microenvironments, and poor clinical outcomes in rectal adenocarcinoma. Single-cell transcriptomic analysis revealed that malignant epithelial cells with elevated expression are metabolically active and closely interact with M2 macrophages. Clinical tissue analyses and functional assays confirmed that is upregulated in rectal cancer and promotes tumor cell proliferation, migration, and M2 macrophage polarization.
This study firstly highlights as a key metabolic and immunological regulator in rectal cancer, with significant prognostic and therapeutic implications. MPGS and may serve as novel biomarkers for risk stratification and guide personalized treatment strategies in patients with rectal adenocarcinoma.
巨噬细胞极化在塑造肿瘤微环境和影响直肠癌进展中起关键作用。然而，调控这一过程的代谢和预后调节因子在很大程度上仍不明确。
我们通过将加权基因共表达网络分析（WGCNA）与多种机器学习算法相结合，在两个独立队列中构建了巨噬细胞极化基因特征（MPGS）：来自GSE87211的363例直肠癌样本和来自癌症基因组图谱（TCGA）的177例样本。在直肠癌和多种其他癌症类型中评估了MPGS的预后性能。采用功能分析、单细胞RNA测序、临床标本免疫组织化学和细胞试验来研究MPGS核心基因在肿瘤生物学和免疫调节中的作用。
MPGS表现出强大的预后能力，并有效预测了对免疫治疗和各种化疗药物的反应。MPGS及其核心代谢成分均与M2巨噬细胞浸润、免疫抑制性肿瘤微环境以及直肠腺癌的不良临床结局密切相关。单细胞转录组分析表明，表达升高的恶性上皮细胞具有代谢活性，并与M2巨噬细胞密切相互作用。临床组织分析和功能试验证实，在直肠癌中上调，并促进肿瘤细胞增殖、迁移和M2巨噬细胞极化。
本研究首次强调作为直肠癌中的关键代谢和免疫调节因子，具有重要的预后和治疗意义。MPGS和可能作为新的生物标志物用于风险分层，并指导直肠腺癌患者的个性化治疗策略。
