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This long-lasting modification either enhances or reduces the innate immune response to subsequent heterologous infections or inflammatory insults. While TII often provides protective benefits, including enhanced protection against pathogens and tumors, it can contribute to maladaptive inflammation in certain conditions. Epigenetic changes and metabolic reprogramming are key drivers of innate immune memory, but it is important to distinguish between transient acute changes and persistent modifications that define bona fide innate immune memory. Innate immune memory can be induced centrally, through systemic events that train hematopoietic progenitors in the bone marrow, or locally, via tissue-resident cells such as macrophages. The presence of trained tissue-resident immune cells offers significant advantages, but their responses may not always result in universally enhanced protection. This review explores recent advances in the understanding of tissue-resident memory macrophages and TII at barrier tissue sites, including the lung, skin, gut, and peritoneum, highlighting the implications for vaccine and immunotherapeutic strategies. Ongoing research promises to accelerate progress in this field and inform new clinical and vaccinology approaches.<\/jats:p>","DOI":"10.7554\/elife.106549","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T15:15:16Z","timestamp":1759850116000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.106549","source":"Crossref","is-referenced-by-count":15,"title":["Resident memory macrophages and trained innate immunity at barrier tissues"],"prefix":"10.7554","volume":"14","author":[{"given":"Alisha","family":"Kang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02fa3aq29","id-type":"ROR","asserted-by":"publisher"}],"name":"McMaster Immunology Research Centre, Department of Medicine, M.G. 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