Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization

Zhiguang Chang; Xuan Guo; Xuefei Li; Yan Wang; Zhongsheng Zang; Siyu Pei; Weiqi Lu; Yang Li; Jian-Dong Huang; Yichuan Xiao; Chenli Liu (刘陈立)

doi:10.1016/j.cell.2025.02.002

Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization

Zhiguang Chang (Co-first Author)
, Xuan Guo (Co-first Author)
, Xuefei Li (Co-first Author)
, Yan Wang (Co-first Author)
, Zhongsheng Zang (Co-first Author)
, Siyu Pei
, Weiqi Lu
, Yang Li
, Jian-Dong Huang
, Yichuan Xiao^*
, Chenli Liu (刘陈立)^*

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

88 Citations (Scopus)

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-10R^hi 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-10R^hi 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. © 2025 Elsevier Inc.

Original language	English
Pages (from-to)	1842-1857.e20
Journal	Cell
Volume	188
Issue number	7
Online published	3 Mar 2025
DOIs	https://doi.org/10.1016/j.cell.2025.02.002
Publication status	Published - 3 Apr 2025

Funding

We are grateful to Drs. Matthew Wook Chang, Haiyun Gan, Jun Qin, and Shuangyin Wang for valuable comments. We thank Dr. Zheng Zhang and Dr. Qian Chen for their help in bacterial migration experiments and Dr. Yongfeng Yang, Dr. Fei Yan, and Mr. Ning Ren for providing valuable suggestions and support for the PET-CT experiments measuring tumor hypoxia. We thank Ms. Andong Caoqian for her assistance in the analysis of transcriptomic studies. Special thanks to Drs. Meng Cao and Zhijian Cai for kindly gifting us the Tlr2 \u2212/\u2212 , Tlr4 \u2212/\u2212 , and Stat3-flox mice. This work was financially supported by the National Key R&D Program of China ( 2018YFA0902701 , 2018YFA0902703 , and 2024YFA1803103 ), the Strategic Priority Research Program ( XDPB0305 and XDB39030300 ), the Key Research Program ( KFZD-SW-216 ) of the Chinese Academy of Sciences, the National Natural Science Foundation of China ( 81802869 , 82030041 , and 82425026 ), the CAS Project for Young Scientist in Basic Research ( YSBR-076 ), Shenzhen grants ( JCYJ20170818164139781 and KQTD2015033117210153 ), and Shanghai grants ( 20XD1424600 and 21140905000 ).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

bacterial immunotherapy
CD8+ T cells
hysteresis
IL-10R
solid tumor microenvironment
synthetic biology

ESI Highly Cited Papers

Highly Cited Paper 2026
Highly Cited Paper 2025

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10.1016/j.cell.2025.02.002Licence: Elsevier user license

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title = "Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization",

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. {\textcopyright} 2025 Elsevier Inc.",

keywords = "bacterial immunotherapy, CD8+ T cells, hysteresis, IL-10R, solid tumor microenvironment, synthetic biology",

author = "Zhiguang Chang and Xuan Guo and Xuefei Li and Yan Wang and Zhongsheng Zang and Siyu Pei and Weiqi Lu and Yang Li and Jian-Dong Huang and Yichuan Xiao and \{Chenli Liu (刘陈立)\}",

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doi = "10.1016/j.cell.2025.02.002",

language = "English",

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Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization. / Chang, Zhiguang (Co-first Author); Guo, Xuan (Co-first Author); Li, Xuefei (Co-first Author) et al.
In: Cell, Vol. 188, No. 7, 03.04.2025, p. 1842-1857.e20.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization

AU - Chang, Zhiguang

AU - Guo, Xuan

AU - Li, Xuefei

AU - Wang, Yan

AU - Zang, Zhongsheng

AU - Pei, Siyu

AU - Lu, Weiqi

AU - Li, Yang

AU - Huang, Jian-Dong

AU - Xiao, Yichuan

AU - Chenli Liu (刘陈立), null

PY - 2025/4/3

Y1 - 2025/4/3

N2 - 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. © 2025 Elsevier Inc.

AB - 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. © 2025 Elsevier Inc.

KW - bacterial immunotherapy

KW - CD8+ T cells

KW - hysteresis

KW - IL-10R

KW - solid tumor microenvironment

KW - synthetic biology

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DO - 10.1016/j.cell.2025.02.002

M3 - RGC 21 - Publication in refereed journal

C2 - 40037354

SN - 0092-8674

VL - 188

SP - 1842-1857.e20

JO - Cell

JF - Cell

IS - 7

ER -

Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization

Abstract

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UN SDGs

Research Keywords

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