Faculty, Staff and Student Publications

Publication Date

6-9-2025

Journal

Cancer Cell

DOI

10.1016/j.ccell.2025.04.003

PMID

40345189

PMCID

PMC12151776

PubMedCentral® Posted Date

6-6-2026

PubMedCentral® Full Text Version

Post-print

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

Animals, Hepatitis A Virus Cellular Receptor 2, Humans, Mice, Adenocarcinoma of Lung, Lung Neoplasms, Tumor Microenvironment, Precancerous Conditions, Single-Cell Analysis, Gene Expression Profiling, Immunity, Innate, Multiomics, TIM-3, cancer prevention, imaging mass cytometry, immune landscape, lung adenocarcinoma evolution, precancer, spatial single cell, stage dependent

Published Open-Access

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