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

doi:10.1016/j.ccell.2025.04.003

. 2025 Jun 9;43(6):1125-1140.e10.

doi: 10.1016/j.ccell.2025.04.003. Epub 2025 May 8.

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

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

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

Bo Zhu et al. Cancer Cell. 2025.

. 2025 Jun 9;43(6):1125-1140.e10.

doi: 10.1016/j.ccell.2025.04.003. Epub 2025 May 8.

Authors

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.

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Conflict of interest statement

Declaration of interests J. Zhang reports research funding from Merck, Johnson and Johnson, Novartis, Summit, Hengenix and consultant fees from BMS, Johnson and Johnson, AstraZeneca, Geneplus, OrigMed, Innovent, Varian, Catalyst outside the submitted work. I.I.W reports Honoraria from Genentech/Roche, Bayer, Bristol-Myers Squibb, Astra Zeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Oncocyte, Flame, and MSD; Research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adapt immune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, and Akoya. J.V.H. reports honorariums from AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche and Leads Biolabs. A.M. receives royalties from a patent has been licensed from Johns Hopkins University to ThriveEarlier Detection (an Exact Science Company). The other authors declare no competing interests.

References

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[1] Siegel RL, Miller KD, Wagle NS, and Jemal A (2023). Cancer statistics, 2023. CA Cancer J Clin 73, 17–48. 10.3322/caac.21763. - DOI - PubMed

[2] Siegel RL, Miller KD, Wagle NS, and Jemal A (2023). Cancer statistics, 2023. CA Cancer J Clin 73, 17–48. 10.3322/caac.21763. - DOI - PubMed

[3] Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, and Sicks JD (2011). Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365, 395–409. 10.1056/NEJMoa1102873. - DOI - PMC - PubMed

[4] Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, and Sicks JD (2011). Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365, 395–409. 10.1056/NEJMoa1102873. - DOI - PMC - PubMed

[5] Thai AA, Solomon BJ, Sequist LV, Gainor JF, and Heist RS (2021). Lung cancer. Lancet 398, 535–554. 10.1016/S0140-6736(21)00312-3. - DOI - PubMed

[6] Thai AA, Solomon BJ, Sequist LV, Gainor JF, and Heist RS (2021). Lung cancer. Lancet 398, 535–554. 10.1016/S0140-6736(21)00312-3. - DOI - PubMed

[7] Weichert W, and Warth A (2014). Early lung cancer with lepidic pattern: adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. Curr Opin Pulm Med 20, 309–316. 10.1097/MCP.0000000000000065. - DOI - PubMed

[8] Weichert W, and Warth A (2014). Early lung cancer with lepidic pattern: adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. Curr Opin Pulm Med 20, 309–316. 10.1097/MCP.0000000000000065. - DOI - PubMed

[9] Tomonaga N, Nakamura Y, Yamaguchi H, Ikeda T, Mizoguchi K, Motoshima K, Doi S, Nakatomi K, Iida T, Hayashi T, et al. Analysis of Intratumor Heterogeneity of EGFR Mutations in Mixed Type Lung Adenocarcinoma. Clin Lung Cancer 14, 521–526. S1525–7304(13)00072–7 [pii] 10.1016/j.cllc.2013.04.005. - DOI - PubMed

[10] Tomonaga N, Nakamura Y, Yamaguchi H, Ikeda T, Mizoguchi K, Motoshima K, Doi S, Nakatomi K, Iida T, Hayashi T, et al. Analysis of Intratumor Heterogeneity of EGFR Mutations in Mixed Type Lung Adenocarcinoma. Clin Lung Cancer 14, 521–526. S1525–7304(13)00072–7 [pii] 10.1016/j.cllc.2013.04.005. - DOI - PubMed

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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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