Abstract SY28-03: Intrinsic and extrinsic inflammatory signaling spatiotemporally orchestrate lung cancer adeno-to-squamous transition and RAS(ON) inhibitor resistance

Abstract Adeno-to-Squamous Transition (AST) is established as therapeutic resistance mechanism, especially in STK11/LKB1-mutant lung adenocarcinoma (LUAD) patients treated with KRAS inhibitors. However, how tumor-intrinsic and microenvironmental cues coordinate to drive AST and drug resistance remains unclear. Through integrative analyses of single-cell transcriptomics data of Kras/Lkb1 mouse tumors and human adenosquamous carcinomas, we here show that intrinsic and extrinsic inflammatory signaling triggered by oxidative stress spatiotemporally orchestrates AST. Transient activation of NF-κB signaling by oxidative stress sustains LUAD identity and survival at early adenomatous stage, whereas IL-1α secreted by tumor cells at double-positive (DP) transitioning state reprograms cancer associated fibroblasts (CAFs) into leukocyte-associated CAFs which produce IL-1β to promote neutrophil extracellular traps (NETs) formation and tumor growth. NETs compromise the therapeutic efficacy of the RAS(ON) inhibitor RMC-6236, and such drug resistance could be reversed by combined therapy with IL-1 receptor antagonist Anakinra. Collectively, our study not only uncovers intrinsic and extrinsic inflammatory signaling spatiotemporally orchestrating squamous transition and targeted therapy resistance, but also provides promising strategies to overcome AST-mediated drug resistance. Citation Format: Hongbin Ji. Intrinsic and extrinsic inflammatory signaling spatiotemporally orchestrate lung cancer adeno-to-squamous transition and RAS(ON) inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY28-03.