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The solid pattern representing poorly differentiated LUAD is linked to poor prognosis and therapeutic resistance. To uncover underlying mechanisms, we integrate bulk and single\u2010cell RNA sequencing and identify a preferential enrichment of interleukin 4 induced 1 (IL4I1)\u2010expressing tumor\u2010associated macrophages (TAMs) and tryptophan 2,3\u2010dioxygenase (TDO2)\u2010expressing myofibroblastic cancer\u2010associated fibroblasts (myCAFs) in a solid pattern of LUAD. Spatial transcriptomics reveals their co\u2010localization in peritumoral stroma, forming an immune\u2010excluded niche. Mechanistically, TDO2\u207a myCAFs promoted monocyte\u2010to\u2010IL4I1\u207a TAM differentiation via the kynurenine\u2010aryl hydrocarbon receptor (AhR) axis. Tryptophan metabolomic landscapes confirm that IL4I1\u207a TAMs and TDO2\u207a myCAFs enhance tryptophan degradation and accumulation of AhR ligands (e.g., kynurenine, indole\u20103\u2010carboxaldehyde), contributing to CD8\u207a T cell exhaustion and anti\u2010PD\u20101 therapeutic resistance. IL4I1\u207a TAMs and TDO2\u207a myCAFs conformably mediate ferroptosis resistance through the AhR\u2010NRF2\u2010GPX4\u2010SLC7A11 pathway. Notably, AhR antagonist CH\u2010223191 restores ferroptosis sensitivity of tumor cells. A triple therapy combining CH\u2010223191, ferroptosis inducer (Imidazole ketone erastin or RSL3), and anti\u2010PD\u20101 agent demonstrates superior efficacy and safety in vivo. Together, our findings demonstrate that IL4I1\u207a TAMs and TDO2\u207a myCAFs synergistically establish an immunosuppressive, ferroptosis\u2010resistant niche via AhR signaling in solid predominant LUAD and offer promising therapeutic strategies to reprogram the tumor microenvironment.<\/jats:p>","DOI":"10.1002\/advs.202513606","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T06:16:55Z","timestamp":1766470615000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["IL4I1\u207a Macrophages and TDO2\u207a Myofibroblasts Drive AhR\u2010Mediated Immunosuppression and Ferroptosis Resistance in Solid Predominant Lung Adenocarcinoma"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8169-7978","authenticated-orcid":false,"given":"Zhaoxuan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery The First Affiliated 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