IL4I1⁺ Macrophages and TDO2⁺ Myofibroblasts Drive AhR‐Mediated Immunosuppression and Ferroptosis Resistance in Solid Predominant Lung Adenocarcinoma

ABSTRACT Lung adenocarcinoma (LUAD) displays marked intratumoral heterogeneity with distinct histological patterns. The solid pattern representing poorly differentiated LUAD is linked to poor prognosis and therapeutic resistance. To uncover underlying mechanisms, we integrate bulk and single‐cell RNA sequencing and identify a preferential enrichment of interleukin 4 induced 1 (IL4I1)‐expressing tumor‐associated macrophages (TAMs) and tryptophan 2,3‐dioxygenase (TDO2)‐expressing myofibroblastic cancer‐associated fibroblasts (myCAFs) in a solid pattern of LUAD. Spatial transcriptomics reveals their co‐localization in peritumoral stroma, forming an immune‐excluded niche. Mechanistically, TDO2⁺ myCAFs promoted monocyte‐to‐IL4I1⁺ TAM differentiation via the kynurenine‐aryl hydrocarbon receptor (AhR) axis. Tryptophan metabolomic landscapes confirm that IL4I1⁺ TAMs and TDO2⁺ myCAFs enhance tryptophan degradation and accumulation of AhR ligands (e.g., kynurenine, indole‐3‐carboxaldehyde), contributing to CD8⁺ T cell exhaustion and anti‐PD‐1 therapeutic resistance. IL4I1⁺ TAMs and TDO2⁺ myCAFs conformably mediate ferroptosis resistance through the AhR‐NRF2‐GPX4‐SLC7A11 pathway. Notably, AhR antagonist CH‐223191 restores ferroptosis sensitivity of tumor cells. A triple therapy combining CH‐223191, ferroptosis inducer (Imidazole ketone erastin or RSL3), and anti‐PD‐1 agent demonstrates superior efficacy and safety in vivo. Together, our findings demonstrate that IL4I1⁺ TAMs and TDO2⁺ myCAFs synergistically establish an immunosuppressive, ferroptosis‐resistant niche via AhR signaling in solid predominant LUAD and offer promising therapeutic strategies to reprogram the tumor microenvironment.