Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD

Chi Ma, Qiong Fu, Laurence P. Diggs, John C. McVey, Justin McCallen, Simon Wabitsch, Benjamin Ruf, Zachary Brown, Bernd Heinrich, Qianfei Zhang, Umberto Rosato, Sophie Wang, Linda Cui, Jay A. Berzofsky, David E. Kleiner, Dale B. Bosco, Long Jun Wu, Chunwei Walter Lai, Yaron Rotman, Changqing XieFirouzeh Korangy, Tim F. Greten

Research output: Contribution to journalArticlepeer-review


Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L−/− platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8+ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.

Original languageEnglish (US)
Pages (from-to)986-998.e5
JournalCancer cell
Issue number9
StatePublished - Sep 12 2022


  • CD40L
  • HCC
  • P2Y12
  • liver metastasis
  • platelets

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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