Dichotomous Immunogenetic Landscape of Lung Adenocarcinoma Associated with Usual Interstitial Pneumonia.

Abstract Background: Interstitial pneumonia increases the risk of lung cancer; however, the underlying carcinogenic pathways remain poorly understood. Usual interstitial pneumonia (UIP) frequently co-localizes with lung adenocarcinoma (LADC), providing a model to understand chronic inflammation-driven carcinogenesis. Method: We conducted whole-genome and RNA sequence of 44 UIP (+) LADCs and compared them with 216 UIP (-) LADCs. To address intra-tumoral heterogeneity and characterize the tumor microenvironment, we performed spatial transcriptomics using a whole-transcriptome platform (Visium, 55 µm resolution) and single-cell-resolution platforms (Xenium lung panel, 302 genes; Xenium 5K, 5,018 genes). Results: UIP (+) LADCs exhibited unique molecular features: low tumor mutation burden, absence of EGFR mutations, and a pervasive presence of myofibroblastic cancer-associated fibroblasts (myCAFs), likely derived from fibrotic myofibroblasts in UIP. The most common genetic alteration was in NKX2-1 (41%), encoding the lung-lineage transcription factor TTF-1. A dichotomous immunogenetic landscape was observed: NKX2-1-deficient tumors showed gastrointestinal differentiation, frequent ERBB2 amplification with super-enhancer formation, and immune "cold" characteristics; NKX2-1-proficient tumors exhibited immune "hot" characteristics with abundant intra-tumoral CD8+ T cells and elevated PD-L1 expression. Spatial transcriptomics analysis revealed intratumor heterogeneity associated with NKX2-1 expression status, suggesting illegitimate gastrointestinal differentiation. In addition, the presence of WNT5A- and CTHRC1-expressing myCAFs were identified, which may originate from UIP-associated myofibroblasts. Paired tumor and UIP regions demonstrated that CTHRC1+WNT5A+ myCAF population was markedly enriched in tumor tissues relative to matched UIP regions, suggesting their expansion during carcinogenesis. Conclusion: We propose a dual model of UIP-associated lung carcinogenesis determined by NKX2-1 status, wherein myCAFs derived from UIP-associated myofibroblasts drive both carcinogenic pathways. These findings offer targeted therapeutic strategies based on the dichotomous immunogenetic landscape and highlight targeting the myofibroblast-to-myCAF transition as a potential approach for cancer prevention in chronic pulmonary fibrosis. Citation Format: Akifumi Mochizuki, Ayako Suzuki, Kouya Shiraishi, Masahiro Torasawa, Takayuki Honda, Susumu Kirimura, Yasunari Miyazaki, Kenichi Okubo, Syuzo Kaneko, Yukihiro Yoshida, Shun-ichi Watanabe, Masahiro Tsuboi, Genichiro Ishii, Issei Imoto, Ryuji Hamamoto, Yasushi Yatabe, Yutaka Suzuki, Takashi Kohno. Dichotomous immunogenetic landscape of lung adenocarcinoma associated with usual interstitial pneumonia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2272.