Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes

Nat Commun. 2018 Aug 24;9(1):3417. doi: 10.1038/s41467-018-05979-8.


Cancer immunotherapy can induce durable antitumor responses. However, many patients poorly respond to such therapies. Here we describe a generic antitumor therapy that is based on the intratumor delivery of mRNA that codes for the necroptosis executioner mixed lineage kinase domain-like (MLKL) protein. This intervention stalls primary tumor growth and protects against distal and disseminated tumor formation in syngeneic mouse melanoma and colon carcinoma models. Moreover, MLKL-mRNA treatment combined with immune checkpoint blockade further improves the antitumor activity. MLKL-mRNA treatment rapidly induces T cell responses directed against tumor neo-antigens and requires CD4+ and CD8+ T cells to prevent tumor growth. Type I interferon signaling and Batf3-dependent dendritic cells are essential for this mRNA treatment to elicit tumor antigen-specific T cell responses. Moreover, MLKL-mRNA treatment blunts the growth of human lymphoma in mice with a reconstituted human adaptive immune system. MLKL-based treatment can thus be exploited as an effective antitumor immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Cell Line
  • Female
  • Humans
  • Immunotherapy / methods*
  • Lymphoma / immunology
  • Lymphoma / therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Necrosis / genetics
  • Necrosis / metabolism*
  • Neoplasms / genetics
  • Neoplasms / therapy*
  • Proportional Hazards Models
  • Protein Kinases / genetics*
  • RNA, Messenger / genetics*
  • Signal Transduction / genetics
  • Signal Transduction / physiology


  • RNA, Messenger
  • MLKL protein, human
  • Protein Kinases