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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Di Conza, G; Tsai, C-H; Gallart-Ayala, H; Yu, Y-R; Franco, F; Zaffalon, L; Xie, X; Li, X; Xiao, Z; Raines, LN; Falquet, M; Jalil, A; Locasale, JW; Percipalle, P; Masson, D; Huang, SC-C; Martinon, F; Ivanisevic, J; Ho, P-C

Published Date

  • November 2021

Published In

Volume / Issue

  • 22 / 11

Start / End Page

  • 1403 - 1415

PubMed ID

  • 34686867

Pubmed Central ID

  • PMC7611917

Electronic International Standard Serial Number (EISSN)

  • 1529-2916

Digital Object Identifier (DOI)

  • 10.1038/s41590-021-01047-4


  • eng

Conference Location

  • United States