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- Sustained macrophage reprogramming is required for CD8+ T cell–dependent long-term tumor eradicationPublication . Jardim, Carolina; Bica, Marta; Reis-Sobreiro, Mariana; Mota, Afonso Teixeira da; Lopes, Raquel; Ferreira-Pinto, Miguel Alexandre; Sousa, Neuza S.; Mensurado, Sofia; Boekhoff, Henning; Scolaro, Tommaso; Reugebrink, Maud; Gonçalves-Sousa, Natacha; Kubo, Hiroshi; Leites, Elvira; Morais, Vanessa A.; Silva-Santos, Bruno; Barbosa-Morais, Nuno; Serre, KarineTumor-associated macrophages (TAM) exhibit a dual role in tumor progression and antitumor immunity. However, understanding the functional states and molecular mechanisms of antitumor TAMs remains a challenge. Herein, we show that intratumoral administration of a combination of agonists against TLR3 and CD40 [hereafter termed myeloid cell treatment (MCT)] reprogrammed TAMs in situ to adopt a protective antitumor phenotype in an orthotopic mouse breast cancer model, and that this led to tumor regression. Single-cell RNA sequencing of TAMs from different tumor stages and after MCT revealed a transient antitumor TAM phenotype, present at 12 hours after MCT and characterized by markers such as inducible nitric oxide synthase and CD38, which was replaced by TAMs coexpressing tumor-limiting and tumor-promoting features by 72 hours after MCT. Maintenance of antitumor TAMs required repeated MCT administration, and this promoted the activation of CD8+ T cells and long-term tumor eradication. Mechanistically, reactive oxygen species and TNF-α were pivotal in TAM-mediated tumor control. Our findings uncover the vulnerability of transient TAM reprogramming and show that it can be overcome by repeated MCT administrations to sustain efficient antitumor immune responses.