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Background Inflammation is a hallmark of cancer initiation and therapeutic resistance. We previously demonstrated that targeting myeloid-derived inflammation by dual checkpoint blockade can reinvigorate response to immune checkpoint inhibitor (ICI) and stereotactic body radiotherapy (SBRT) in a preclinical model of triple-negative breast cancer (TNBC). Given that T cell function is a key variable underlying treatment efficacy to ICI, we sought to understand the impact of targeting myeloid-derived inflammation on T cell responses and T cell receptor (TCR) clonal expansion at single-cell resolution.Methods We used the orthotopic syngeneic EO771 murine model of TNBC, which is resistant to ICI therapy targeting the PD-1/PD-L1 axis. C57BL/6 tumor-bearing mice were treated with SBRT (16 Gy x 1 using the X-RAD SmART platform) and anti-PD-1 (clone RMP1-14) with or without anti-CD47 (clone MIAP301). CD4 + and CD8+ tumor-infiltrating lymphocytes (TILs) were isolated from treated EO771 tumors by magnetic activated cell sorting and processed for single-cell RNA sequencing (scRNA-seq) and TCR sequencing (TCR-seq) per 10x Genomics protocols. scRNA-seq data were analyzed using Seurat (v5.2.1) and BBrowserX (Bioturing) with TCR clonotype integration using scRepertoire (v2.2.1).Results In total, we sequenced 13,914 TILs from EO771 tumors treated with ICI monotherapy or dual checkpoint blockade. By unsupervised clustering, we identified six populations of TILs including conventional CD4 + T cells, naïve-like CD8+ T cells, T regulatory cells (Tregs), early activation CD8+ T cells, effector memory T cells, and exhausted CD8+ T cells. We found that dual checkpoint blockade expanded effector memory T cells (CCR7, TCF7, CXCR6) and exhausted CD8+ T cells (PDCD1, HAVCR2, IFNG). Within the CD8+ compartment, differential expression (DE) analysis revealed an upregulation of survival and cytotoxicity-associated genes including BCL2, CD44, and GZMB with dual checkpoint blockade, indicating enhanced effector potential and survival capacity. Although dual checkpoint blockade was associated with increased Treg infiltration, DE analysis revealed a downregulation of immunosuppressive and metabolic regulators including HAVCR2, PRF1, and IL10RA. Lastly, by TCR profiling, we observed enhanced clonal TCR expansion specifically within the CD8+ T cell populations with dual checkpoint blockade, which was mapped to effector memory and exhausted subsets.Conclusions Compared to ICI monotherapy, dual checkpoint blockade targeting myeloid-derived inflammation can enhance antitumor immunity by reprogramming T cell landscape in in a preclinical model of TNBC. These results highlight the potential to repurpose anti-CD47 therapy to promote effector T cell function, induce CD8 + T cell clonal expansion, and mitigate the immunosuppressive activity of Tregs.