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Drug\u2010induced immunogenic cell death (ICD) is a promising approach. However, its efficacy is curtailed by limited tumor\u2010cell targeting with collateral immune\u2010cell damage and by overactive efferocytosis that rapidly removes ICD\u2010associated danger signals, thereby restricting antitumor immunity. Herein, we develop a microenvironment\u2010responsive nanocarrier co\u2010delivering both PLK1 inhibitor (BI6727) and TIM\u20103 inhibitor (ML\u2010T7). It integrates dual\u2010bioeffect of synthetic lethal selective ICD and whole\u2010immuno system remodelling initiated by effective macrophage efferocytosis inhibition. In detail, the molecular hallmark differences between tumor and immune cells was utilized to provide high\u2010quality antigens. Meanwhile, the nanotherapeutic enables serial phagocyte regulations, such as, suppressed macrophage phagocytosis, enhanced antigen recognition and phagocytosis by dendritic cells (DCs), and then alleviated T cell exhaustion. The underlying mechanism of nanotherapeutics\u2010mediated overall immune system reprogramming was explored by transcriptional profile analyses. These findings indicate that precise molecularly targeted ICD combined with coordinated immune activation enables efficient primary tumor suppression and promotes T\u2010cell phenotypes associated with antitumor immune memory, providing a novel paradigm for cancer immunotherapy.<\/jats:p>","DOI":"10.1002\/smll.76306","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T11:06:18Z","timestamp":1792062378000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Nanodelivery Platform Harnessing Synthetic Lethality and Efferocytosis Inhibition for Synergistically Enhanced Immunotherapy of Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1083-0727","authenticated-orcid":false,"given":"Huawei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery State Key Laboratory of Cardiology and Medical Innovation Center The Institute for Biomedical Engineering &amp; Nano Science School of Medicine Shanghai East Hospital Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3019-3072","authenticated-orcid":false,"given":"Shengming","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery State Key Laboratory of Cardiology and Medical Innovation Center The Institute for Biomedical Engineering &amp; Nano Science School of Medicine Shanghai East Hospital Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery State Key Laboratory of Cardiology and Medical Innovation Center The Institute for Biomedical Engineering &amp; Nano Science School of Medicine Shanghai East Hospital Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery State Key Laboratory of Cardiology and Medical Innovation Center The Institute for Biomedical Engineering &amp; Nano Science School of Medicine Shanghai East Hospital Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenlong","family":"He","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery State Key Laboratory of Cardiology and Medical Innovation Center The Institute for Biomedical Engineering &amp; Nano Science School of Medicine Shanghai East Hospital Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9164-9072","authenticated-orcid":false,"given":"Hongyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery Shanghai East Hospital School of Medicine Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery Shanghai East Hospital School of Medicine Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyue","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery State Key Laboratory of Cardiology and Medical Innovation Center The Institute for Biomedical Engineering &amp; Nano Science School of Medicine Shanghai East Hospital Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3618-2794","authenticated-orcid":false,"given":"YuAn","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery Shanghai East Hospital School of Medicine Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Surgical Intensive Care Unit School of Medicine Xinhua Hospital Shanghai Jiaotong University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7483-9296","authenticated-orcid":false,"given":"Yilong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery State Key Laboratory of Cardiology and Medical Innovation Center The Institute for Biomedical Engineering &amp; Nano Science School of Medicine Shanghai East Hospital Tongji University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010pathol\u2010042420\u2010093238"},{"key":"e_1_2_8_3_1","article-title":"Advances in Systemic Therapies for Triple Negative Breast Cancer","volume":"381","author":"Leon\u2010Ferre R. A.","year":"2023","journal-title":"Bmj\u2010British Medical Journal"},{"key":"e_1_2_8_4_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.tranon.2024.101893","article-title":"Small Molecule Agents for Triple Negative Breast Cancer: Current Status and Future Prospects","volume":"41","author":"Ou Y.","year":"2024","journal-title":"Translational Oncology"},{"key":"e_1_2_8_5_1","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2019.37.15_suppl.e12049","article-title":"Chemotherapy\u2010Related Outcomes in Triple\u2010Negative Breast Cancer","volume":"37","author":"Wellmann R. 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Current Scenario and Future Perspectives","volume":"11","author":"Barchiesi G.","year":"2021","journal-title":"Frontiers in Oncology"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.81847"},{"key":"e_1_2_8_16_1","doi-asserted-by":"crossref","first-page":"9038","DOI":"10.7150\/thno.63416","article-title":"Mapping the Landscape of Synthetic Lethal Interactions in Liver Cancer","volume":"11","author":"Yang C.","year":"2021","journal-title":"Theranostics"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010022\u201000470\u2010y"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.08.001"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010020\u20100232\u20101"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102020\u2010001408"},{"key":"e_1_2_8_21_1","doi-asserted-by":"crossref","DOI":"10.1002\/smsc.202400479","article-title":"Targeting Frequent Efferocytosis in Tumor Microenvironment Is a New Direction for Cancer Treatment","volume":"5","author":"Zhu G. X.","year":"2025","journal-title":"Small Science"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2024.01.004"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003626\u20109"},{"key":"e_1_2_8_24_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2024.107458","article-title":"The Role of Tim\u20103 Blockade in the Tumor Immune Microenvironment Beyond T Cells","volume":"209","author":"Zhang J.","year":"2024","journal-title":"Pharmacological Research"},{"key":"e_1_2_8_25_1","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2017.1385690","article-title":"Blockade of Tim\u20103 Binding to Phosphatidylserine and CEACAM1 Is a Shared Feature of Anti\u2010Tim\u20103 Antibodies That Have Functional Efficacy","volume":"7","author":"Sabatos\u2010Peyton C. 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