Lu Xiaoqin, Ren Dan, Zhao Panpan, Li Yanfang, Wang Zhenhui, Zhang Jingyan
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Front Immunol. 2025 May 6;16:1565924. doi: 10.3389/fimmu.2025.1565924. eCollection 2025.
Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment, regulating immune escape and promoting cancer progression. Understanding the role of phagocytosis regulators in female-specific cancers is essential for developing effective therapeutic strategies.
We performed comprehensive analyses of public databases to evaluate the expression, somatic mutations, and copy number variations of phagocytosis regulators. DNA methylation patterns, biological pathways, survival outcomes, and drug sensitivity were assessed. Additionally, immune modulators, immune cell infiltration, and single-cell sequencing were used to explore alterations in phagocytosis and their cellular origins. The functional role of HMGB2 in tumor cell behavior was validated through assays.
Phagocytosis regulators exhibited differential expression across various female-specific cancers, with key genes such as CD47 and FOXO1 playing significant roles in modulating tumor progression. High-frequency mutations were found in PTEN, ARID1A, and UBR4. Genes like COX5B and MS4A1 emerged as potential predictors of clinical outcomes and therapeutic response. HMGB2 knockdown significantly inhibited cancer cell proliferation, migration, and invasion in female-specific cancers. HMGB2 knockdown in macrophages led to a significant impairment in phagocytosis of breast, cervical, ovarian, and endometrial cancer cells. Furthermore, when HMGB2 knockdown was combined with Palbociclib treatment, a significant decrease in tumor cell proliferation was observed across multiple cancer models.
This study highlights the pivotal role of phagocytosis regulators, particularly HMGB2, in the progression of female-specific cancers. Targeting HMGB2 offers promising therapeutic opportunities, potentially enhancing precision oncology and improving patient outcomes.
肿瘤相关巨噬细胞（TAM）在肿瘤微环境中发挥着关键作用，调节免疫逃逸并促进癌症进展。了解吞噬作用调节因子在女性特异性癌症中的作用对于制定有效的治疗策略至关重要。
我们对公共数据库进行了全面分析，以评估吞噬作用调节因子的表达、体细胞突变和拷贝数变异。评估了DNA甲基化模式、生物途径、生存结果和药物敏感性。此外，使用免疫调节剂、免疫细胞浸润和单细胞测序来探索吞噬作用的改变及其细胞起源。通过实验验证了HMGB2在肿瘤细胞行为中的功能作用。
吞噬作用调节因子在各种女性特异性癌症中表现出差异表达，CD47和FOXO1等关键基因在调节肿瘤进展中发挥着重要作用。在PTEN、ARID1A和UBR4中发现了高频突变。COX5B和MS4A1等基因成为临床结果和治疗反应的潜在预测指标。HMGB2基因敲低显著抑制了女性特异性癌症中癌细胞的增殖、迁移和侵袭。巨噬细胞中HMGB2基因敲低导致对乳腺癌、宫颈癌、卵巢癌和子宫内膜癌细胞的吞噬作用显著受损。此外，当HMGB2基因敲低与哌柏西利治疗联合使用时，在多个癌症模型中观察到肿瘤细胞增殖显著降低。
本研究强调了吞噬作用调节因子，特别是HMGB2，在女性特异性癌症进展中的关键作用。靶向HMGB2提供了有前景的治疗机会，可能增强精准肿瘤学并改善患者预后。
