中国科学院深圳先进技术研究院刘陈立团队揭示了利用IL-10R滞后性进行吞噬逃避和肿瘤免疫恢复的细菌免疫疗法。2025年3月3日出版的《细胞》杂志发表了这项成果。
通过利用这种双重熟练程度的工程肠沙门氏菌菌株，研究小组揭示了一个潜在的单一机制。具体来说，白细胞介素-10受体（IL-10R）表达的滞后非线性驱动肿瘤浸润的免疫细胞进入肿瘤特异性IL-10Rhi状态。细菌利用这一点增强产生IL-10的肿瘤相关巨噬细胞，逃避肿瘤相关中性粒细胞的吞噬，同时扩大和刺激先前存在的衰竭肿瘤驻留CD8+ T细胞。这种有效的组合可以消除肿瘤，防止复发，并抑制多种肿瘤类型的转移。对人类样本的分析表明，IL-10Rhi状态可能是人类肿瘤类型中普遍存在的特征。他们的研究揭示了细菌免疫疗法在实体瘤中的双重挑战背后未解决的机制，并为瘤内免疫调节提供了一个框架。
据介绍，细菌免疫疗法具有抗癌潜力。然而，解锁其功能需要对细菌如何逃避抗微生物免疫防御和刺激肿瘤微环境（TME）内的抗肿瘤免疫反应有一个机制的理解。
附：英文原文
Title: Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization
Author: Zhiguang Chang, Xuan Guo, Xuefei Li, Yan Wang, Zhongsheng Zang, Siyu Pei, Weiqi Lu, Yang Li, Jian-Dong Huang, Yichuan Xiao, Chenli Liu
Issue&Volume: 2025-03-03
Abstract: Bacterial immunotherapy holds promising cancer-fighting potential. However, unlocking its power requires a mechanistic understanding of how bacteria both evade antimicrobial immune defenses and stimulate anti-tumor immune responses within the tumor microenvironment (TME). Here, by harnessing an engineered Salmonella enterica strain with this dual proficiency, we unveil an underlying singular mechanism. Specifically, the hysteretic nonlinearity of interleukin-10 receptor (IL-10R) expression drives tumor-infiltrated immune cells into a tumor-specific IL-10Rhi state. Bacteria leverage this to enhance tumor-associated macrophages producing IL-10, evade phagocytosis by tumor-associated neutrophils, and coincidently expand and stimulate the preexisting exhausted tumor-resident CD8+ T cells. This effective combination eliminates tumors, prevents recurrence, and inhibits metastasis across multiple tumor types. Analysis of human samples suggests that the IL-10Rhi state might be a ubiquitous trait across human tumor types. Our study unveils the unsolved mechanism behind bacterial immunotherapy’s dual challenge in solid tumors and provides a framework for intratumoral immunomodulation.
DOI: 10.1016/j.cell.2025.02.002
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00158-8