{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T17:46:28Z","timestamp":1776620788750,"version":"3.51.2"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":49,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Immune checkpoint blockade (ICB) targeting PD-1\/PD-L1 axis has transformed breast cancer treatment, yet how therapy reshapes the tumor microenvironment (TME) through cell\u2013cell communication (CCC) remains unclear. Existing CCC inference methods relying on correlations have difficulty distinguishing genuine signaling from confounded associations. Here, we present a causal inference framework that uses single-cell data and leverages treatment as an instrumental variable to identify genuine CCC networks, referred to as scIVCCC, which infers causal signal transduction across cell types. Applying scIVCCC to single-cell RNA-seq data from 31 breast cancer patients before and after anti-PD-1 therapy, we constructed causal CCC networks linking exhausted T cells to tumor-associated macrophages (TAMs). Our analysis reveals a dual role of T cell-macrophage crosstalk: CD4+ and CD8+ exhausted T cells drive anti-tumor M1-like TAMs activation via TNF\u2013TNFRSF1A, TNFSF14\u2013LTBR, and ICAM1\u2013ITGAL\/ITGB2. Conversely, they also induce immunosuppressive M2-like polarization through pathways such as TNF\u2013TNFRSF1B (TNFR2), TNFSF14\u2013TNFRSF14 (HVEM), and RPS19\u2013C5AR1, which likely contribute to therapeutic resistance. Our causal modeling suggests that receptors within these networks, such as C5AR1, TNFR2, and CSF1R, may serve as potential candidates for combination therapies to enhance anti-PD-1 efficacy. Collectively, these findings demonstrate that scIVCCC offers a robust framework for dissecting treatment-induced CCC dynamics and prioritizing actionable targets for clinical translation.<\/jats:p>","DOI":"10.1093\/bib\/bbag139","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T12:52:23Z","timestamp":1776430343000},"source":"Crossref","is-referenced-by-count":0,"title":["Causal modeling reveals cell\u2013cell communication dynamics in the tumor microenvironment during anti-PD-1 therapy in breast cancer patients"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4575-8364","authenticated-orcid":false,"given":"Aodong","family":"Qiu","sequence":"first","affiliation":[{"name":"Department of Biomedical Informatics, University of Pittsburgh , 5607 Baum Blvd, Pittsburgh, PA, 15206 ,","place":["United States"]},{"name":"School of Medicine, Tsinghua Medicine, Tsinghua University , No. 30, Shuangqing Road, Haidian District, Beijing, 100084 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, University of Pittsburgh , 5607 Baum Blvd, Pittsburgh, PA, 15206 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph D","family":"Ramsey","sequence":"additional","affiliation":[{"name":"Department of Philosophy, Carnegie Mellon University , 5000 Forbes Avenue, Pittsburgh, PA, 15213 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryan","family":"Andrews","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Behavioral Sciences, University of Minnesota , 2312 S 6th St, Minneapolis, MN, 55454 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boyang","family":"Sun","sequence":"additional","affiliation":[{"name":"Mohamed bin Zayed University of Artificial Intelligence , Building 1B, Masdar City, Abu Dhabi ,","place":["United Arab Emirates"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuangxia","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, University of Pittsburgh , 5607 Baum Blvd, Pittsburgh, PA, 15206 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengyao","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, University of Pittsburgh , 5607 Baum Blvd, Pittsburgh, PA, 15206 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Philosophy, Carnegie Mellon University , 5000 Forbes Avenue, Pittsburgh, PA, 15213 ,","place":["United States"]},{"name":"Mohamed bin Zayed University of Artificial Intelligence , Building 1B, Masdar 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