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Energy metabolism not only fuels immune responses but also fundamentally dictates the functional phenotypes of immune cells through metabolic reprogramming. By systematically integrating metabolic programming data of key immune cells across diverse tissues (skin, gut, nasal, and ocular mucosa), this review constructs a cross-disease \u201cmetabolism\u2013signaling network\u201d atlas. The synthesis highlights that glycolysis and mTORC1 signaling are predominantly coupled with the pro-inflammatory outputs of Th2 cells and ILC2s, whereas fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) sustain the homeostasis of Tregs and M2-like macrophages. Furthermore, this review characterizes how the tryptophan, glutamine, and arginine pathways fine-tune the immune tolerance boundary via the IDO\u2013AhR\u2013mTOR axis. We also elucidate a conserved inter-organ \u201chypoxia\u2013HIF-1\u03b1\u2013lactylation\u201d axis, which, in conjunction with tissue-specific metabolic branches (e.g., the ceramide pathway in the skin, the SCFA circuit in the gut, and the lactate\u2013GPR81 loop in the mucosa), collectively sculpts local microenvironments and remodeling trajectories. Ultimately, a novel diagnostic and therapeutic framework centered on metabolic phenotyping is proposed, providing prospective insights into targeting metabolic checkpoints for precision immunotherapy in type 2 inflammation.<\/jats:p>","DOI":"10.34133\/research.1347","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T03:47:32Z","timestamp":1781063252000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":1,"title":["Type 2 Inflammatory Diseases: The Crossroads of Immunity and Metabolism"],"prefix":"10.34133","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3045-0316","authenticated-orcid":false,"given":"Lin","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Allergy, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, \rChinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China."},{"name":"Optogenetics and Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, \rEast China University of Science and Technology, Shanghai 200237, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1834-5782","authenticated-orcid":false,"given":"Zhou-Xian","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Allergy, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, \rChinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Qi","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, 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