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Systemic immunity is critical for successful cancer immunotherapy; thus, recurrence of NMIBC may be due to suboptimal systemic activation of anti\u2010tumor immunity after local immunotherapy. We previously reported that systemically acquired trained immunity (a form of innate immune memory) in circulating monocytes is associated with increased time\u2010to\u2010recurrence in patients with NMIBC treated with BCG. Herein, we used a mouse model of NMIBC to compare the effects of intravesical versus intravenous (systemic) BCG immunotherapy on the local and peripheral immune microenvironments. We also assessed whether BCG\u2010induced trained immunity modulates anti\u2010tumor immune responses. Compared with intravesical BCG, which led to a tumor\u2010promoting immune microenvironment, intravenous BCG resulted in an anti\u2010tumoral bladder microenvironment characterized by increased proportions of cytotoxic T lymphocytes (CTLs), and decreased proportions of myeloid\u2010derived suppressor cells. Polarization toward anti\u2010tumoral immunity occurred in draining lymph nodes, spleen, and bone marrow following intravenous versus intravesical BCG treatment. Pre\u2010treatment with intravesical BCG was associated with increased rate of tumor growth compared with intravenous BCG pre\u2010treatment. Trained immunity contributed to remodeling of the tumor immune microenvironment, as co\u2010instillation of BCG\u2010trained macrophages with ovalbumin\u2010expressing bladder tumor cells increased the proportion of tumor\u2010specific CTLs. Furthermore, BCG\u2010trained dendritic cells exhibited enhanced antigen uptake and presentation and promoted CTL proliferation. Our data support the concept that systemic immune activation promotes anti\u2010tumor responses, and that BCG\u2010induced trained immunity is important in driving anti\u2010tumor adaptive immunity.<\/jats:p>","DOI":"10.1002\/ijc.34897","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T15:23:59Z","timestamp":1710429839000},"page":"352-364","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Systemic versus localized <scp>Bacillus Calmette Gu\u00e9rin<\/scp> immunotherapy of bladder cancer promotes an anti\u2010tumoral microenvironment: Novel role of trained immunity"],"prefix":"10.1002","volume":"155","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7256-9632","authenticated-orcid":false,"given":"Aline","family":"Atallah","sequence":"first","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen's University  Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3732-8926","authenticated-orcid":false,"given":"Arielle","family":"Grossman","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen's University  Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard W.","family":"Nauman","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen's University  Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Fran\u00e7ois","family":"Par\u00e9","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen's University  Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen's University  Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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