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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.<\/jats:p>","DOI":"10.3390\/cancers16234075","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T06:24:44Z","timestamp":1733379884000},"page":"4075","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A High-Throughput Immune-Oncology Screen Identifies Immunostimulatory Properties of Cytotoxic Chemotherapy Agents in TNBC"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9773-3512","authenticated-orcid":false,"given":"Kennady K.","family":"Bullock","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hasaka","sequence":"additional","affiliation":[{"name":"Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA"},{"name":"High-Throughput Screening Facility, Vanderbilt University, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Days","sequence":"additional","affiliation":[{"name":"Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA"},{"name":"High-Throughput Screening Facility, Vanderbilt University, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8019-900X","authenticated-orcid":false,"given":"Joshua A.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA"},{"name":"High-Throughput Screening Facility, Vanderbilt University, Nashville, TN 37232, USA"},{"name":"Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A.","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9580-900X","authenticated-orcid":false,"given":"Ann","family":"Richmond","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"},{"name":"Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"ref_1","unstructured":"American Cancer Society (2022). 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