Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity

Giusy Di Conza, Chin Hsien Tsai, Hector Gallart-Ayala, Yi Ru Yu, Fabien Franco, Lea Zaffalon, Xin Xie, Xiaoyun Li, Zhengtao Xiao, Lydia N. Raines, Maryline Falquet, Antoine Jalil, Jason W. Locasale, Piergiorgio Percipalle, David Masson, Stanley Ching Cheng Huang, Fabio Martinon, Julijana Ivanisevic, Ping Chih Ho

Research output: Contribution to journalArticlepeer-review

Abstract

Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here, we uncover that tumor-cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, we uncover the unexpected roles of tumor-cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and reveal therapeutic targets for sustaining host antitumor immunity.

Original languageEnglish (US)
Pages (from-to)1403-1415
Number of pages13
JournalNature Immunology
Volume22
Issue number11
DOIs
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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