Defining the cellular and molecular identities of histologic subtypes in lung adenocarcinoma

Tumor histology reflects disease aggressiveness and clinical outcomes in cancer patients. Lung adenocarcinomas (LUADs) are classified based on predominant histologic patterns, including high-grade micropapillary and solid subtypes which portend unfavorable clinical features and prognosis. However, the cellular and molecular characteristics underlying these histologic subtypes remain largely unknown.

We used scRNA-seq to profile 117,266 cells from 18 treatment-naïve LUADs with heterogeneous histologic patterns and also performed spatial transcriptomic analysis (10x Visium) for representative cases. By integrating single-cell transcriptomics with spatial information, we aimed to characterize the cellular identity and spatial organization driving LUAD heterogeneity.

We demonstrated that histologic subtypes can be distinguished by subtype-specific cancer cell subpopulations and immunosuppressive phenotypes in the tumor microenvironment (TME). Our data reveal how intercellular interactions among cancer cells, macrophages, and CD8⁺ T cells in the prognostically unfavorable solid subtype are associated with cancer cell plasticity and promote an immunosuppressive TME. Additionally, we identify HMGA1 as a potential clinically relevant biomarker and therapeutic target for the solid subtype LUAD.

These findings deepen our understanding of the histologic heterogeneity of LUAD and may facilitate the development of subtype-specific biomarkers and targeted therapeutic strategies.