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Simple Summary: Many breast cancers do not respond to immune checkpoint inhibitor therapy, even when combined with the standard of care chemotherapy. Here, we sought to identify compounds that enhance T-cell-mediated toxicity in tumor cells using a high-throughput screen of known anti-cancer drugs. Beginning with a library of over 400 FDA-approved or investigational compounds, we chose four chemotherapy agents for detailed mechanistic follow-up. We describe potential immunostimulatory properties of paclitaxel, bleomycin sulfate, ispinisib, and etoposide. Ultimately, these studies provide insight into the potential immunostimulatory properties of the chosen follow-up compounds and suggest avenues for future investigations into optimizing chemotherapy partners to use with ICI. Background: Triple-negative breast cancers (TNBCs) 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 a crucial need to optimize combining chemotherapy strategies with ICI to enhance overall survival in TNBC. Methods: Therefore, we developed a high-throughput co-culture screening assay to identify compounds that enhance CD8+ T-cell-mediated tumor cell cytotoxicity. Over 400 FDA-approved compounds or agents under investigation for oncology indications were included in the screening library. Results: 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 time points: paclitaxel, bleomycin sulfate, ispinesib, and etoposide. Lead compounds affected the expression of MHCI, MHCII, and PD-L1 and induced markers of immunogenic cell death (extracellular ATP or HMGB1). Conclusions: Based on the 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. [ABSTRACT FROM AUTHOR]