Background Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited targeted therapeutic options and marked heterogeneity in response to immune checkpoint blockade. Shikonin, a natural naphthoquinone compound, has shown antitumor and immunomodulatory activities, but its potential molecular targets and immune-related transcriptional programs in TNBC remain incompletely characterized. Methods We integrated systems pharmacology, TCGA-BRCA bulk transcriptomic data, molecular docking, immune infiltration analysis, prognostic modeling, and single-cell RNA sequencing data from GSE176078. Putative shikonin-associated TNBC targets were identified by intersecting predicted shikonin targets, TNBC-related genes, and differentially expressed genes. Functional enrichment analysis was performed to characterize biological pathways. Candidate immune-related genes were prioritized according to their correlation with CD274 expression. The resulting signature was evaluated for associations with immune checkpoint genes, immune cell infiltration, immune activation, computationally inferred immunotherapy-related phenotypes, and overall survival. Single-cell analysis was used to define the cellular distribution of signature genes within the TNBC tumor microenvironment. Results Seventy candidate shikonin-associated TNBC targets were identified and were enriched in immune-related and oncogenic pathways, including PD-1/PD-L1 checkpoint signaling, chemokine signaling, PI3K-Akt signaling, and MAPK signaling. A CD274-prioritized 10-gene immune signature comprising ITK, CCR4, TAP1, JAK3, PIM2, LYZ, SYK, HCK, SOAT1, and PLA2G7 was identified by integrating positive CD274 correlations, false-discovery-rate control, and established immune relevance. High signature scores were associated with elevated immune checkpoint expression, increased immune infiltration, a stronger immune activation index, and lower predicted immune evasion. Molecular docking provided computational support for potential binding compatibility between shikonin and the encoded proteins. At single-cell resolution, the signature genes were distributed across lymphoid, myeloid, epithelial, and stromal compartments, indicating a multicellular immune-related niche. Conclusion This study identifies a shikonin-associated immune signature that reflects an inflamed and checkpoint-enriched tumor microenvironment in TNBC. These findings provide candidate molecular features and a hypothesis-generating framework for further experimental evaluation of the potential immunomodulatory relevance of shikonin in TNBC.