Related Experiment Video

Updated: Oct 15, 2025

Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
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Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and

Giusy Di Conza1,2, Chin-Hsien Tsai1,2, Hector Gallart-Ayala3

  • 1Department of Oncology, University of Lausanne, Epalinges, Switzerland.

Nature Immunology
|October 23, 2021
PubMed

Insights

Tumor cells use glucosylceramide to induce endoplasmic reticulum (ER) stress in macrophages, promoting tumor growth. Targeting this ER stress pathway offers a new strategy to enhance anti-tumor immunity.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cellular Stress Responses

Background:

  • Tumor-associated macrophages (TAMs) adopt pro-tumorigenic phenotypes, driven by tumor microenvironment cues.
  • Mechanisms by which tumor cells dictate TAM behavior are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which tumor cells influence TAM phenotypes.
  • To identify novel therapeutic targets for modulating TAMs and enhancing anti-tumor immunity.

Main Methods:

  • Investigated the role of tumor-cell-derived glucosylceramide in macrophage ER stress.
  • Utilized genetic manipulation to ablate XBP1 expression in TAMs.
  • Assessed the impact of ER stress modulation on TAM phenotype and survival.

Main Results:

  • Tumor-derived glucosylceramide induces unconventional ER stress in macrophages, leading to IRE1-mediated spliced XBP1 and STAT3 activation.
  • Spliced XBP1 and STAT3 cooperate to enhance pro-tumorigenic and immunosuppressive gene expression in TAMs.
  • Genetic ablation of XBP1 or amelioration of ER stress by LPCAT3 impaired TAM pro-tumorigenic phenotype and survival.

Conclusions:

  • Tumor-cell-produced lipids, specifically glucosylceramide, orchestrate TAM polarization and survival through ER stress induction.
  • Targeting ER stress pathways in TAMs presents a promising therapeutic strategy for cancer treatment and bolstering anti-tumor immunity.

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