SCD1 inhibition promotes lipid peroxidation and enhances anti-PD-1 response in triple-negative breast cancer
- 1Cancer Metabolism and Tumor Microenvironment Laboratory, Interdisciplinary Group for Applied Genoproteomics, University of Liège, Liège, Belgium
- 2Institute for Research in Immunology and Cancer (IRIC), University of Montréal, Montréal, QC, Canada
- 3Laboratory of Tumor and Development Biology Laboratory, Interdisciplinary Group for Applied Genoproteomics, University of Liège, Liège, Belgium
Abstract
Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease that often exhibits a relatively immunologically “cold” tumor microenvironment, which can limit the efficacy of immune checkpoint inhibitors (ICIs). Alterations in lipid metabolism and lipid peroxidation may influence tumor–immune interactions and represent potential determinants of response to immune checkpoint blockade.
Methods: Human TNBC cell lines (MDA-MB-231, BT-549) were treated with ferroptosis inducers (FINs), including RSL3 and SCD1 inhibitor (SCD1i), and cell death was assessed. Proteomic profiling of cell lysates and conditioned media was performed, and IL-8 and MIF secretion was quantified by ELISA. Splenocytes were incubated with conditioned media to assess immune activation via flow cytometry. In vivo efficacy of SCD1i, PD-1 blockade, and their combination was evaluated using the E0771 murine TNBC model.
Results: SCD1i and RSL3 treatment induced the release of inflammatory mediators, including IL-8 and MIF, as confirmed by ELISA. Conditioned media from treated TNBC cells enhanced immune activation in splenocytes, characterized by increased effector CD4+ and CD8+ T-cell populations and altered expression of immune checkpoint receptors. In vivo, SCD1 inhibition increased CD8+ T cell infiltration into the tumor microenvironment and increased PD-1 and LAG-3 expression in both CD4+ and CD8+ T cells. Notably, combined SCD1 inhibition and anti-PD-1 therapy resulted in greater tumor growth inhibition compared with either treatment alone.
Conclusion: SCD1 inhibition promotes lipid peroxidation and release of inflammatory factors that enhance immune activation and sensitize TNBC to checkpoint blockade. Targeting the SCD1 represents a promising strategy to improve ICI efficacy in TNBC.
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BibTeX
@article{garfia2026scd1,
title = {{SCD1 inhibition promotes lipid peroxidation and enhances anti-PD-1 response in triple-negative breast cancer}},
author = {Quentin Herrera Garfia and Aurélien Azam and Eric Bonneil and Laetitia Montero-Ruiz and Mohsen Momeni and Mohammad Farran and Robin Jehay and Nor Eddine Sounni},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1843935},
url = {https://doi.org/10.3389/fimmu.2026.1843935},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SCD1 inhibition promotes lipid peroxidation and enhances anti-PD-1 response in triple-negative breast cancer
AU - Quentin Herrera Garfia
AU - Aurélien Azam
AU - Eric Bonneil
AU - Laetitia Montero-Ruiz
AU - Mohsen Momeni
AU - Mohammad Farran
AU - Robin Jehay
AU - Nor Eddine Sounni
PY - 2026
DA - 2026/10/12
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1843935
UR - https://doi.org/10.3389/fimmu.2026.1843935
AB - Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease that often exhibits a relatively immunologically “cold” tumor microenvironment, which can limit the efficacy of immune checkpoint inhibitors (ICIs). Alterations in lipid metabolism and lipid peroxidation may influence tumor–immune interactions and represent potential determinants of response to immune checkpoint blockade. Methods: Human TNBC cell lines (MDA-MB-231, BT-549) were treated with ferroptosis inducers (FINs), including RSL3 and SCD1 inhibitor (SCD1i), and cell death was assessed. Proteomic profiling of cell lysates and conditioned media was performed, and IL-8 and MIF secretion was quantified by ELISA. Splenocytes were incubated with conditioned media to assess immune activation via flow cytometry. In vivo efficacy of SCD1i, PD-1 blockade, and their combination was evaluated using the E0771 murine TNBC model. Results: SCD1i and RSL3 treatment induced the release of inflammatory mediators, including IL-8 and MIF, as confirmed by ELISA. Conditioned media from treated TNBC cells enhanced immune activation in splenocytes, characterized by increased effector CD4+ and CD8+ T-cell populations and altered expression of immune checkpoint receptors. In vivo, SCD1 inhibition increased CD8+ T cell infiltration into the tumor microenvironment and increased PD-1 and LAG-3 expression in both CD4+ and CD8+ T cells. Notably, combined SCD1 inhibition and anti-PD-1 therapy resulted in greater tumor growth inhibition compared with either treatment alone. Conclusion: SCD1 inhibition promotes lipid peroxidation and release of inflammatory factors that enhance immune activation and sensitize TNBC to checkpoint blockade. Targeting the SCD1 represents a promising strategy to improve ICI efficacy in TNBC.
SN - 1664-3224
ER -