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Chemotherapeutic agents are recognized for their substantial impacts on the gut microbiome, yet their therapeutic potential as microbiome modulators remains uncertain, due to the complexity of microbiome\u2010host\u2010drug interactions. Here, it is showed that low\u2010dose chemotherapy preferentially shapes the ileal microbiome to augment the extraintestinal immune response to anti\u2010programmed death\u20101 (anti\u2010PD\u20101) therapy without causing intestinal toxicity. Mechanistically, low\u2010dose chemotherapy causes DNA damage restricted to highly\u2010proliferative ileal epithelial cells, resulting in the accumulation of cytosolic dsDNA and the activation of the absent in melanoma 2 (AIM2) inflammasome. AIM2\u2010dependent IL\u201018 secretion triggers the interplay between proximal Th1 cells and Paneth cells in ileal crypts, impairing the local antimicrobial host defense and resulting in ileal microbiome change. Intestinal epithelium\u2010specific knockout of AIM2 in mice significantly attenuates CPT\u201011\u2010caused IL\u201018 secretion, Paneth cell dysfunction, and ileal microbiome alteration. Moreover, AIM2 deficiency in mice or antibiotic microbial depletion attenuates chemotherapy\u2010augmented antitumor responses to anti\u2010PD1 therapy. Collectively, these findings provide mechanistic insights into how chemotherapy\u2010induced genomic stress is transduced to gut microbiome change and support the rationale of applying low\u2010dose chemotherapy as a promising adjuvant strategy in cancer immunotherapy with minimal toxicity.<\/jats:p>","DOI":"10.1002\/advs.202304781","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T09:28:10Z","timestamp":1704706090000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Low\u2010Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells"],"prefix":"10.1002","volume":"11","author":[{"given":"Congying","family":"Pu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 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