Early Proinflammatory Niches Drive Lung Adenocarcinoma Initiation

Progression from lung precursor lesions to invasive lung adenocarcinoma (LUAD) remains poorly understood. Peng, Sinjab, Dai, Treekitkarnmongkol, and colleagues applied multimodal spatial-omic analysis to tissue samples from patients with invasive LUAD, representing the range of pathology from normal lung regions to lung adenomatous precursors to invasive lesions, generating high-resolution maps of epithelial and immune cell interactions. Reconstruction of clonal architecture through inferred genome-wide copy-number alterations demonstrated patterns of patient-specific heterogeneity. Furthermore, the earliest clones identified in most cases mapped to reactive pneumocytes, a cell type previously suggested by the authors to function as LUAD progenitor cells. These reactive pneumocytes, which were transcriptionally resembled by KRT8-high alveolar intermediate cells (KAC), were observed to reside in niches enriched with proinflammatory macrophages expressing IL1B. These proinflammatory niches were abundant in atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) but diminished in invasive LUAD. Ligand–receptor analysis highlighted IL1B–IL1R1 signaling as a dominant axis in precursor lesions, particularly in KRAS-mutant cases, where NF-κB and IFN pathways were strongly activated. Functional studies in tobacco carcinogen–induced mouse models of LUAD confirmed that IL1β signaling promoted KAC expansion and tumor initiation. Genetic deletion of Il1r1 or pharmacologic IL1β blockade reduced alveolar progenitors and tumor burden in mouse models. Combining IL1β inhibition with PD-1 blockade during precancerous stages significantly suppressed LUAD development, decreased protumorigenic inflammation, and enhanced CD8+ T-cell infiltration. These findings position epithelial–proinflammatory niches as actionable targets for early interception of LUAD and support clinical strategies integrating antiinflammatory and immunotherapeutic approaches.Peng F, Sinjab A, Dai Y, Treekitkarnmongkol W, Yang S, Gomez Bolanos LI, et al. Multimodal spatial-omics reveal co-evolution of alveolar progenitors and proinflammatory niches in progression of lung precursor lesions. Cancer Cell 2026 Nov 6 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.