Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception

Bo Zhu; Pingjun Chen; Muhammad Aminu; Jian-Rong Li; Junya Fujimoto; Yanhua Tian; Lingzhi Hong; Hong Chen; Xin Hu; Chenyang Li; Natalie Vokes; Andre L Moreira; Don L Gibbons; Luisa M Solis Soto; Edwin Roger Parra Cuentas; Ou Shi; Songhui Diao; Jie Ye; Frank R Rojas; Eduardo Vilar; Anirban Maitra; Ken Chen; Nicolas Navin; Monique Nilsson; Beibei Huang; Simon Heeke; Jianhua Zhang; Cara L Haymaker; Vamsidhar Velcheti; Daniel H Sterman; Veena Kochat; William I Padron; Ludmil B Alexandrov; Zhubo Wei; Xiuning Le; Linghua Wang; Junya Fukuoka; J Jack Lee; Ignacio I Wistuba; Harvey I Pass; Mark Davis; Samir Hanash; Chao Cheng; Steven Dubinett; Avrum Spira; Kunal Rai; Scott M Lippman; P Andrew Futreal; John V Heymach; Alexandre Reuben; Jia Wu; Jianjun Zhang

doi:10.1016/j.ccell.2025.04.003

Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception

Cancer Cell. 2025 Jun 9;43(6):1125-1140.e10. doi: 10.1016/j.ccell.2025.04.003. Epub 2025 May 8.

Authors

Bo Zhu¹, Pingjun Chen², Muhammad Aminu³, Jian-Rong Li⁴, Junya Fujimoto⁵, Yanhua Tian¹, Lingzhi Hong⁶, Hong Chen¹, Xin Hu⁷, Chenyang Li⁷, Natalie Vokes⁶, Andre L Moreira⁸, Don L Gibbons⁶, Luisa M Solis Soto⁹, Edwin Roger Parra Cuentas⁹, Ou Shi⁹, Songhui Diao³, Jie Ye⁶, Frank R Rojas⁹, Eduardo Vilar¹⁰, Anirban Maitra¹¹, Ken Chen¹², Nicolas Navin¹³, Monique Nilsson⁶, Beibei Huang¹⁴, Simon Heeke⁶, Jianhua Zhang⁷, Cara L Haymaker⁹, Vamsidhar Velcheti¹⁵, Daniel H Sterman¹⁶, Veena Kochat⁷, William I Padron⁷, Ludmil B Alexandrov¹⁷, Zhubo Wei⁶, Xiuning Le⁶, Linghua Wang⁷, Junya Fukuoka¹⁸, J Jack Lee¹⁹, Ignacio I Wistuba⁹, Harvey I Pass²⁰, Mark Davis²¹, Samir Hanash²², Chao Cheng⁴, Steven Dubinett²³, Avrum Spira²⁴, Kunal Rai⁷, Scott M Lippman²⁵, P Andrew Futreal⁷, John V Heymach⁶, Alexandre Reuben⁶, Jia Wu³, Jianjun Zhang²⁶

Affiliations

¹ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Institute for Data Science in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
⁵ Clinical Research Center in Hiroshima, Hiroshima University Hospital, Hiroshima, Japan.
⁶ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Pathology, NYU Langone Health, New York, NY, USA.
⁹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Department of Translational Molecular Pathology and Sheikn Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹² Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁵ Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA.
¹⁶ Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA; Cardiothoracic Surgery, NYU Grossman School of Medicine, New York, NY, USA.
¹⁷ Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, USA.
¹⁸ Department of Pathology Informatics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
¹⁹ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁰ Department of Cardiothoracic Surgery, NYU Langone Health, New York, NY, USA.
²¹ Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
²² Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, CA, USA.
²³ Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
²⁴ Pathology & Laboratory Medicine, and Bioinformatics, Boston University, Boston, MA, USA.
²⁵ UC San Diego School of Medicine, La Jolla, CA, USA.
²⁶ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jzhang20@mdanderson.org.

PMID: 40345189
PMCID: PMC12151776 (available on 2026-06-09)
DOI: 10.1016/j.ccell.2025.04.003

Abstract

How tumor microenvironment shapes lung adenocarcinoma (LUAD) precancer evolution remains poorly understood. Spatial immune profiling of 114 human LUAD and LUAD precursors reveals a progressive increase of adaptive response and a relative decrease of innate immune response as LUAD precursors progress. The immune evasion features align the immune response patterns at various stages. TIM-3-high features are enriched in LUAD precancers, which decrease in later stages. Furthermore, single-cell RNA sequencing (scRNA-seq) and spatial immune and transcriptomics profiling of LUAD and LUAD precursor specimens from 5 mouse models validate high TIM-3 features in LUAD precancers. In vivo TIM-3 blockade at precancer stage, but not at advanced cancer stage, decreases tumor burden. Anti-TIM-3 treatment is associated with enhanced antigen presentation, T cell activation, and increased M1/M2 macrophage ratio. These results highlight the coordination of innate and adaptive immune response/evasion during LUAD precancer evolution and suggest TIM-3 as a potential target for LUAD precancer interception.

Keywords: TIM-3; cancer prevention; imaging mass cytometry; immune landscape; lung adenocarcinoma evolution; precancer; spatial single cell; stage dependent.

MeSH terms

Adenocarcinoma of Lung* / drug therapy
Adenocarcinoma of Lung* / genetics
Adenocarcinoma of Lung* / immunology
Adenocarcinoma of Lung* / metabolism
Adenocarcinoma of Lung* / pathology
Animals
Gene Expression Profiling
Hepatitis A Virus Cellular Receptor 2* / antagonists & inhibitors
Hepatitis A Virus Cellular Receptor 2* / genetics
Hepatitis A Virus Cellular Receptor 2* / immunology
Hepatitis A Virus Cellular Receptor 2* / metabolism
Humans
Immunity, Innate
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / immunology
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Mice
Multiomics
Precancerous Conditions* / genetics
Precancerous Conditions* / immunology
Precancerous Conditions* / metabolism
Precancerous Conditions* / pathology
Single-Cell Analysis
Tumor Microenvironment / immunology

Substances

Hepatitis A Virus Cellular Receptor 2
HAVCR2 protein, human
Havcr2 protein, mouse

Grants and funding

R01 CA234629/CA/NCI NIH HHS/United States