Triple-negative breast cancers (TNBC) typically have a greater immune cell infiltrate and are more likely to respond to immune checkpoint inhibition (ICI) than ER+ or HER2+ breast cancers. However, there is crucial need to optimize combining chemotherapy strategies with ICI to enhance overall survival TNBC. Therefore, we developed a high-throughput co-culture screening assay to identify compounds enhancing CD8+T-cell-mediated tumor cell cytotoxicity, screening over 400 FDA-approved compounds or agents under investigation for oncology indications. Four chemotherapy agents were chosen as priority hits for mechanistic follow-up due to their ability to enhance T-cell mediated cytotoxicity at multiple doses and multiple timepoints: paclitaxel, bleomycin sulfate, ispinesib and etoposide. Lead compounds affected expression of MHCI, MHCII, and PD-L1, and induced markers of immunogenic cell death (extracellular ATP or HMGB1). Based on ability to increase tumor cell susceptibility to T-cell mediated cytotoxicity, while minimizing T-cell toxicity, bleomycin was identified as the most promising lead candidate. Overall, the results of these studies provide mechanistic insight into potential new chemotherapy partners to enhance anti-PD-1 efficacy in TNBC patients.