Yin Lijie, Dong Yue, Luo Renjie, Li Jingman, Wang Jiali, Dou Huan, Zhao Guangfeng, Hou Yayi
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China.
Cell Oncol (Dordr). 2025 Apr 9. doi: 10.1007/s13402-025-01063-8.
Patients who survive the excessive inflammatory phase of sepsis experience prolonged immunoparalysis/immunosuppression. During this phase, the patient's immune system is severely impaired, which increases the patient's susceptibility to septic complications. Sepsis survivors have a significantly greater incidence of cancer, but the mechanism underlying this phenomenon is unknown.
We constructed two sepsis-melanoma models to assess the relationship between sepsis and sepsis-related concomitant cancer. In our investigation, we employed a range of experimental technique to elucidate the intricate mechanisms through which the immunoparalysis phase of sepsis facilitates melanoma progression. Furthermore, we induced trained immunity with oroxylin A (OA) to evaluate its ability to reverse immunoparalysis and subsequent tumor progression in sepsis-melanoma models.
We showed that sepsis upregulated the serum level of interleukin (IL)-6 and the number of myeloid-derived suppressor cells (MDSCs), regulated G-MDSCs/M-MDSCs and inhibited CD8T-cell function, which promoted melanoma progression. OA-induced trained immunity can reverse immunoparalysis, maintain the antitumor capacity of the immune system, and inhibit the development of sepsis-complicated melanoma. Notably, OA can target macrophage migration inhibitory factor (MIF) and downregulate the serum level of IL-6, which may be a crucial molecular mechanism by which OA induces trained immunity to reverse the immunoparalysis phase of sepsis.
Sepsis can promote cancer progression by upregulating MIF and IL-6, increasing the G-MDSCs/M-MDSCs ratio and reducing the number and function of CD8 T cells, leading to immunoparalysis, while trained immunity can alleviate this progression. The findings of this study provide new strategies for preventing or treating sepsis-complicated cancer.
脓毒症过度炎症期存活的患者会经历长时间的免疫麻痹/免疫抑制。在此阶段，患者的免疫系统严重受损，这增加了患者发生脓毒症并发症的易感性。脓毒症幸存者患癌症的发生率显著更高，但这一现象背后的机制尚不清楚。
我们构建了两个脓毒症-黑色素瘤模型，以评估脓毒症与脓毒症相关伴随癌症之间的关系。在我们的研究中，我们采用了一系列实验技术来阐明脓毒症免疫麻痹期促进黑色素瘤进展的复杂机制。此外，我们用木犀草素A（OA）诱导训练免疫，以评估其在脓毒症-黑色素瘤模型中逆转免疫麻痹及随后肿瘤进展的能力。
我们发现脓毒症上调了白细胞介素（IL）-6的血清水平和髓源性抑制细胞（MDSC）的数量，调节了粒细胞-髓源性抑制细胞/单核细胞-髓源性抑制细胞（G-MDSC/M-MDSC），并抑制了CD8T细胞功能，从而促进了黑色素瘤的进展。OA诱导的训练免疫可逆转免疫麻痹，维持免疫系统的抗肿瘤能力，并抑制脓毒症并发黑色素瘤的发展。值得注意的是，OA可靶向巨噬细胞迁移抑制因子（MIF）并下调IL-6的血清水平，这可能是OA诱导训练免疫以逆转脓毒症免疫麻痹期的关键分子机制。
脓毒症可通过上调MIF和IL-6、增加G-MDSC/M-MDSC比例以及减少CD8 T细胞数量和功能来促进癌症进展，导致免疫麻痹，而训练免疫可缓解这一进展。本研究结果为预防或治疗脓毒症并发癌症提供了新策略。
