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Using CITE-seq single-cell transcriptomics and trajectory analysis, the study shows that neoadjuvant low-dose metronomic chemotherapy drives co-evolution of divergent myeloid subsets in triple-negative breast cancer (TNBC). CXCL16+ myeloid proportions increase and high STAT1 regulon activity marks PD-L1–expressing immature myeloid cells. STAT1 inhibition sensitizes MCT-primed tumors to ICB, supporting STAT1 modulation with anti-PD-1 as a pre-clinical strategy.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/targeting-cxcl16-and-stat1-augments-immune-checkpoint-blockade-therapy-in-triple-negative-breast-cancer-received-and-accepted-article-summary/382276/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/targeting-cxcl16-and-stat1-augments-immune-checkpoint-blockade-therapy-in-triple-negative-breast-cancer-received-and-accepted-article-summary/382276.png","ImageObject",300,407,{"name":92,"@type":93},"Hazel","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main focus of the article in TNBC treatment?","Question",{"text":112,"@type":113},"It investigates how targeting CXCL16 and STAT1-related signaling modulates immune checkpoint blockade therapy in triple-negative breast cancer.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does neoadjuvant low-dose metronomic chemotherapy (MCT) affect myeloid cells?",{"text":117,"@type":113},"MCT induces a characteristic co-evolution of divergent myeloid subsets, increasing CXCL16+ myeloid cells and generating high STAT1 regulon activity in PD-L1–expressing immature myeloid cells.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the reported impact of inhibiting STAT1 signaling in MCT-primed tumors?",{"text":121,"@type":113},"Chemical inhibition of STAT1 sensitizes TNBC to immune checkpoint blockade, highlighting STAT1’s role in shaping the tumor immune microenvironment.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},382276,1790318406,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},137441390410,"https://ap-avatar.wpscdn.com/avatar/2000252f4ab5702993?_k=1776741390130283984","Article [https://doi.org/10.1038/s41467-023-37727-y](https://doi.org/10.1038/s41467-023-37727-y)  \nTargeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer  \nReceived: 25 January 2022  \n\n| Accepted: 27 March 2023 |\n| --- |\n| |\n| Check for updates |\n\nBhavana Palakurthi1,2, Shaneann R. Fross1,2, Ian H. Guldner1,2,  \nEmilija Aleksandrovic 1,2, Xiyu Liu1,2, Anna K. Martino 1, Qingfei Wang 1,2, Ryan A. Neff1, Samantha M. Golomb1,2, Cheryl Lewis 3, Yan Peng3,  \nErin N. Howe1,2 & Siyuan Zhang 1,2,3,4   \nChemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1’s role in modulating TIME. In summary, we leverage singlecell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.  \nCancer is a heterogeneous disease. As such, a systemic view of cancer as an evolving ecosystem, rather than a singular view of specific cell type or gene, is essential to guide a more effective and sustained anticancer treatment1. The divergent response to anti-cancer immunotherapy among patients highlighted an urgent need for systemic interrogation of the dynamic tumor ecosystem due to the nature of immune regulation – a dynamic equilibrium, balancing the immunogenic and immunosuppressive/tolerogenic signals1–3. Myeloid cells are prominent regulators of immune equilibrium vital to normal tissue homeostasis and tumor progression2. Their diverse roles in tuning tumor immune microenvironment (TIME) have been increasingly recognized as critical, sometimes decisive factors, for an optimal antitumor immunotherapy response4.  \nGrowing literature suggests a perplexing antagonistic/compensatory/redundant phenotypic plasticity among different myeloid cell subsets under various cancer contexts -from the binary M1/M2 paradigm and functionally-defined myeloid-derived suppressor cells (MDSC) to the ever growing characterization of the sub-types of myeloid cells2,5. Myeloid cells are extremely heterogeneous and plastic in response to the cues imposed from TIME and systemic anti-cancer treatment6. For instance, PARP inhibitors (in triple-negative breast cancer (TNBC)) mediate glucose and lipid reprogramming and enhance both anti- and pro-tumorigenic features of macrophages through sterol regulatory element-binding protein-1 pathway7. Similarly, expansion of immunosuppressive M2-like macrophages and contraction of inflammatory-macrophages during advanced renal cell  \n1Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA. 2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN 46617, USA. 3Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. 4Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA. e-mail: [Siyuan.Zhang@UTSouthwestern.edu](Siyuan.Zhang@UTSouthwestern.edu)  \ncarcinoma leads to decreased T-cell receptor clonality8. It is clear that the coordinated interplay between heteroge","cbCaissvXkdkVOAF","https://ap.wps.com/l/cbCaissvXkdkVOAF","pdf",4734527,17,"English","# Introduction\n## Rationale for systemic interrogation of the tumor ecosystem\n## Myeloid plasticity and regulation of TIME\n# Results\n## MCT improves T-myeloid spatial proximity\n## Chemotherapy priming and dynamic myeloid homeostasis\n## STAT1 signaling modulation to enhance anti-PD-1 efficacy","[{\"question\":\"What is the main focus of the article in TNBC treatment?\",\"answer\":\"It investigates how targeting CXCL16 and STAT1-related signaling modulates immune checkpoint blockade therapy in triple-negative breast cancer.\"},{\"question\":\"How does neoadjuvant low-dose metronomic chemotherapy (MCT) affect myeloid cells?\",\"answer\":\"MCT induces a characteristic co-evolution of divergent myeloid subsets, increasing CXCL16+ myeloid cells and generating high STAT1 regulon activity in PD-L1–expressing immature myeloid cells.\"},{\"question\":\"What is the reported impact of inhibiting STAT1 signaling in MCT-primed tumors?\",\"answer\":\"Chemical inhibition of STAT1 sensitizes TNBC to immune checkpoint blockade, highlighting STAT1’s role in shaping the tumor immune microenvironment.\"}]","Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer - Received and Accepted Article Summary | PDF",1790249827,43]