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Background: The long duration of treatment and emerging drug resistance pose significant challenges for global tuberculosis eradication efforts. Therefore, novel strategies to shorten TB treatment regimens are urgently needed. Methods: Using an albumin fusion strategy, we created an albumin-fused granulocyte-macrophage colony stimulating factor (named albGM-CSF) novel molecule that harnesses albumin's long-half life and targeting abilities to enhance the biostability of GM-CSF and direct it to the lymph nodes where the effects of GM-CSF can increase dendritic cell populations crucial to eliciting a potent immune response. Findings: In our study, we found that subcutaneous administration of albGM-CSF reduces the mean lung bacillary burden in mice chronically-infected with tuberculosis. This effect was dependent on both innate immunity and CD4 T cells. GM-CSF induced IL-1β release from Mtb-infected dendritic cells and macrophages, and higher IL-1β levels were observed in albGM-CSF-treated mice with chronic TB infection. Interpretation: Albumin fusion with GM-CSF represents a promising tissue-targeting strategy for controlling chronic lung TB infections and serves as a novel in situ therapeutic vaccination platform for other infectious diseases and malignancies. Funding Statement: This research was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R21AI22922. Declarations of Interest: The authors declare no conflict of interest. Ethics Approval Statement: All procedures were performed according to the Johns Hopkins Institutional Animal Care and Use Committee and in accordance with recommendations for proper use and care of laboratory animals.