---
title: "SCD1 inhibition and anti-PD-1 in triple-negative breast cancer: article available but full text no"
id: "frontiers-in-immunology-16-scd1-inhibition-promotes-lipid-peroxidation-and-enhances-anti-pd-1-response-in"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-16-scd1-inhibition-promotes-lipid-peroxidation-and-enhances-anti-pd-1-response-in"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1843935"
published_at: "2026-10-12T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# SCD1 inhibition and anti-PD-1 in triple-negative breast cancer: article available but full text no
## Provenance & Clinical Metadata
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- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1843935)
- **Published At:** 2026-10-12T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The only available source material for this article is the article title and journal metadata; the full research text was not included in the provided source. - The title indicates a focus on **SCD1** inhibition, increased **lipid peroxidation**, and enhanced response to **anti-PD-1** therapy in **triple-negative breast cancer** (TNBC), but no experimental details were provided in the source. - The source did not report preclinical or clinical study design, dosing regimens, model systems, sample sizes, or statistical outcomes; investigators' methods remain unspecified in the supplied content. - No primary endpoints, secondary endpoints, biomarker panels, or safety/toxicity data were included in the source material given to this task. - Key mechanistic claims that could be expected from the title (for example, whether SCD1 inhibition directly increased lipid peroxidation in tumor cells or modulated immune infiltrates) are not documented in the provided extract. - The absence of data prevents confirmation of whether findings derive from in vitro assays, animal models, translational patient samples, or an interventional clinical trial; the source did not report which was used. - Critical next steps for readers: consult the full Frontiers in Immunology article for methods, quantitative results, and limitations; check for reported adverse events, reproducibility measures, and any described biomarkers of response. - The supplied material allows only hypothesis framing and outlines specific unanswered questions clinicians and researchers should expect the full text to address.
## Clinical Analysis & Structured Key Points
Frontiers | SCD1 inhibition promotes lipid peroxidation and enhances anti-PD-1 response in triple-negative breast cancer ORIGINAL RESEARCH article Front. Immunol. , 12 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1843935 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Community Series in Implications of Immune Landscape in Tumor Microenvironment: Volume II 46k views 11 articles Editor & Reviewers Edited by S P Selvarangan Ponnazhagan Reviewed by W Z Weian Zhu M K Maryam Kazerani Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Figure 6 View in article Figure 7 View in article Table 1 Breast cancer cell response to ferroptosis inducers in vitro (IC50). View in article Table 2 Ferroptosis inducers promote the release of proteins involved in immune cell regulation. View in article ORIGINAL RESEARCH article Front. Immunol. , 12 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1843935 SCD1 inhibition promotes lipid peroxidation and enhances anti-PD-1 response in triple-negative breast cancer Q H Quentin Herrera Garfia 1 † A A Aurélien Azam 1 † E B Eric Bonneil 2 L M Laetitia Montero-Ruiz 1,3 M M Mohsen Momeni 1 M F Mohammad Farran 1 R J Robin Jehay 1 N E Nor Eddine Sounni 1 * 1. Cancer Metabolism and Tumor Microenvironment Laboratory, Interdisciplinary Group for Applied Genoproteomics, University of Liège, Liège, Belgium 2. Institute for Research in Immunology and Cancer (IRIC), University of Montréal, Montréal, QC, Canada 3. Laboratory of Tumor and Development Biology Laboratory, Interdisciplinary Group for Applied Genoproteomics, University of Liège, Liège, Belgium See more Article metrics View details 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. 1 Introduction Breast cancer is the most common type of cancer in women, and triple-negative breast cancer (TNBC), which does not express estrogen (ER), progesterone (PR), and human epidermal growth factor receptor-2 (HER2), accounts for 15-20% of cases and is the type of breast cancer with the poorest prognosis ( 1 ). The standard treatment for TNBC is chemotherapy, as this type of cancer does not respond to hormone and targeted therapies because it does not express ER, PR, and HER2. Notably, the immunogenicity of TNBC is heterogeneous, with only a subset of tumors exhibiting an immune-active tumor microenvironment characterized by prominent lymphocyte infiltration within the tumor microenvironment ( 2 ). This enhanced immunogenicity has been associated with elevated immune-related gene expression signatures and increased levels of tumor-infiltrating lymphocytes (TILs) observed in TNBC tumors compared with other breast cancer subtypes ( 3 ). However, TNBC cells also express high levels of programmed cell death-ligand 1 (PD-L1), making the microenvironment highly immunosuppressive ( 4 ). Immunotherapy has therefore emerged as an important therapeutic option for TNBC. Atezolizumab, an anti-PD-L1 antibody, received accelerated FDA approval in 2019 for PD-L1-positive metastatic TNBC; this indication was subsequently withdrawn in the United States. Pembrolizumab, an anti-PD-1 antibody, was approved by the FDA in 2020 for PD-L1-positive unresectable or metastatic TNBC and in 2021 for high-risk early-stage TNBC in combination with chemotherapy, an indication that was not restricted to PD-L1-high disease. Nevertheless, the clinical benefit of immune checkpoint blockade remains heterogeneous, highlighting the need to identify biomarkers and therapeutic strategies that can improve treatment response ( 5 , 6 ). Ferroptosis is a non-apoptotic cell death mechanism linked to an accumulation of peroxidized lipids, mainly polyunsaturated fatty acids (PUFAs), in the cell membrane, leading to its rupture ( 7 ). Lipid peroxidation is strongly linked to iron and reactive oxygen species (ROS) levels in the cell. To inhibit ferroptosis, cells have developed several mechanisms, including lipid detoxification via the enzyme GPX4, using glutathione. Several ferroptosis inducers have therefore been developed to inhibit this detoxification, for example erastin, an inhibitor of SLC7A11, the transporter of cysteine in the cell, which is essential for the formation of glutathione, and RAS selective lethal 3 (RSL3), an inhibitor of GPX4 ( 8 ). Ferroptosis resistance has been recognized as a key contributor to drug resistance in breast cancer, particularly in response to hormone therapy, through mechanisms involving the GPX4-dependent pathway ( 9 , 10 ). In addition, alterations in lipid metabolism have emerged as important drivers of therapeutic resistance through enhanced de novo lipid synthesis ( 11 ). More recent studies have also identified a GPX4-independent mechanism of ferroptosis resistance mediated by stearoyl-CoA desaturase-1 (SCD1), which shifts the balance of PUFAs toward monounsaturated fatty acids (MUFAs), thereby reducing lipid peroxidation and ferroptotic sensitivity ( 12 ). Importantly, ferroptotic cancer cells have been shown to stimulate antitumor immune responses through the release of damage-associated molecular patterns and activation of dendritic cells, suggesting a potential link between ferroptosis and cancer immunotherapy ( 13 ). However, cancer cells frequently develop ferroptosis resistance through metabolic adaptations in lipid metabolism, including pathways regulated by SCD1, which modulates the balance between polyunsaturated and monounsaturated fatty acids and reduces susceptibility to lipid peroxidation ( 12 ). Targeting SCD1 may therefore represent a potential strategy to overcome ferroptosis resistance while simultaneously enhancing antitumor immune responses in TNBC. Apoptotic cell death communicates with immune cells via “find-me” and “eat-me” signals ( 14 ). By contrast, the immunological consequences of alternative cell death modalities, including ferroptosis, remain poorly understood. Here, we found that ferroptotic tumor cells release a distinct secretome including oxidized lipid species, macrophage migration inhibitory factor (MIF), and IL-8. Conditioned medium from TNBC cells undergoing SCD1 inhibition enhanced effector CD4 + and CD8 + T cell activation in splenic cultures and reduced immune checkpoint expression markers. In vivo , SCD1 inhibition increased T cell infiltration into the tumor microenvironment but was accompanied by compensatory upregulation of PD-1 and LAG-3 expression in CD4+ and CD8+ T cells, suggesting a compensatory checkpoint response. Thus, SCD1 inhibition enhances T cell infiltration while simultaneously inducing checkpoint upregulation, highlighting a dynamic balance between immunostimulatory and immunosuppressive signals. Accordingly, combining SCD1 inhibition with anti-PD-1 immunotherapy enhanced T cell–mediated anti-tumor responses and produced greater tumor growth inhibition than either treatment alone. Collectively, these findings suggest that SCD1 inhibition promotes lipid peroxidation and a ferroptosis-associated secretory program that stimulates antitumor immunity while simultaneously eliciting compensatory checkpoint signaling. Targeting SCD1 in combination with immune checkpoint blockade may therefore represent a promising strategy to enhance immunotherapy efficacy in TNBC. 2 Materials and methods 2.1 Cell culture Human breast cancer cells (MDA-MB-231, BT-549, SK-BR-3, HCC-1954, MCF-7, T47-D) and the murine mammary cancer cell line, E0771, were purchased from American Type Culture Collection (ATCC) (Manassas, Virginia, USA). Cell line authentication for interspecies contamination was performed by Leibniz-Institute, Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) (Braunschweig, Germany). Cell lines were tested by MycoALert Kit 139 (Lonza – Basel, Switzerland) to ensure that they were Mycoplasma-free before in vitro and in vivo experiments. MCF7, SK-BR-3, BT-549 and MDA-MB-231 cells were grown in Dulbecco’s modified Eagles’s medium (DMEM) (10938025, Thermofisher, Waltham, Massachusetts, USA), supplemented with 10% fetal bovine serum (FBS) (10270-106, ThermoFisher), L-glutamine (2 mM) (25030-24, ThermoFisher) and 1% Penicillin-Streptomycin (15140-122, ThermoFisher) at 37 °C, in a 5% CO2 humid atmosphere. HCC1954, T47-D and E0771 were grown in Roswell Park Memorial Institute (RPMI) 1640 medium (21875-034, Thermofisher), supplemented with 10% FBS, and 1% Penicillin-Streptomycin at 37 °C, in a 5% CO 2 humid atmosphere. Treatments. To induce ferroptosis, cells were treated with erastin (HY-15763, MedChemExpress, New Jersey, USA), RSL3 (HY-100218A, MedChemExpress) or an inhibitor of Stearoyl-CoA desaturase 1 (SCD1i) (T4515, TargetMol Chemicals Inc, Massachusetts, USA). To inhibit ferroptosis, Deferoxamine (Def) (50µM) (HY-B1625, MedChemExpress) was administered 2 h prior to ferroptosis inducers (FINs) treatment. Apoptosis was induced using Staurosporine (STS) (100nM) (HY-15141, MedChemExpress), and the cells were treated with Z-VAD-FMK (50µM) (HY-16658B, MedChemExpress) 2 h prior to STS treatment to inhibit apoptosis. All drugs were diluted in dimethylsulfoxide (DMSO), with a final DMSO concentration below 0.2% in all vitro experiments. 2.2 Cell proliferation assays and IC 50 calculations IC50 of various FINs, erastin, RSL3 and SCD1i, were calculated by proliferation assays using the Incucyte SX5 (Sartorius, Goettingen, Germany). Cells (5000/well) were seeded in triplicate per condition in a 96-well plate and confluency was measured at day 1 before treatment and every day until 3 days after treatment. SPY650-DNA (1/1.000) (SC501, TebuBio, Le Perray-en-Yvelines, France) and SYTOX™ Green Nucleic Acid Stain (20nM) (S7020, Invitrogen, Carlsbad, California, USA) were added to the culture medium 2 h before the first scan to label total cell nuclei and dead cells, respectively. 2.3 Determination of lipid peroxidation levels BODIPY™ 581/591 C11 is a fluorescent probe designed to detect lipid peroxidation in living cells. Its lipophilicity allows it to incorporate into lipid-rich regions, such as cell membranes. Lipid peroxidation causes a shift in the fluorescent emission peak of the probe from approximately 590 nm (red) to approximately 510 nm (green). Breast cancer cells were treated with FINs for 6 and 24 h, then washed with PBS, trypsinized, and incubated with the fluorescent probe BODIPY™ 581/591 C11 (D3861, ThermoFisher) for 30 minutes at 37 °C and 5% CO 2 . The cells were then analyzed by flow cytometry to observe the shift toward green of the probe. 2.4 Proteomic analysis MDA-MB-231 cells were treated in Petri dishes with SCD1i (15 µM), or RSL3 (1 µM) for 6 or 24 hours. SCD1i and RSL3 were diluted in DMEM medium without FBS. At the end of treatment, the conditioned media at 24 h, as well as the cell pellets at 6 and 24 hours, were collected and stored at -80 °C until analysis. Samples were reconstituted in 50 mM ammonium bicarbonate with 10 mM TCEP [Tris(2-carboxyethyl) phosphine hydrochloride; Thermo Fisher Scientific], and vortexed for 1 h at 37 °C. Chloroacetamide (Sigma-Aldrich) was added for alkylation to a final concentration of 55 mM. Samples were vortexed for another hour at 37 °C. One microgram of trypsin was added, and digestion was performed for 8 h at 37 °C. Samples were dried down and solubilized in 4% formic acid (FA). Peptides were loaded and separated on a home-made reversed-phase column (150-μm i.d. by 200 mm) with a 56-min gradient from 10 to 30% ACN-0.2% FA and a 600-nl/min flow rate on an Easy nLC-1000 connected to an Orbitrap Fusion (Thermo Fisher Scientific, San Jose, CA). Each full MS spectrum acquired at a resolution of 120,000 was followed by tandem-MS (MS-MS) spectra acquisition on the most abundant multiply charged precursor ions for a maximum of 3s. Tandem-MS experiments were performed using collision-induced dissociation (CID) at a collision energy of 30%. The data were processed using PEAKS X Pro (Bioinformatics Solutions, Waterloo, ON) and a Uniprot human database (20366 entries). Mass tolerances on precursor and fragment ions were 10 ppm and 0.3 Da, respectively. Fixed modification was carbamidomethyl (C). Variable selected posttranslational modifications were oxidation (M), deamidation (NQ), phosphorylation (STY) along acetylation (N-ter). Two sample t-test were performed to get log2 of the fold change and –log of p-values. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD082708 and 10.6019/PXD082708. 2.5 Enzyme-linked immunosorbent assay MDA-MB-231 (3.10 5 ) and E0771 (4.10 5 ) cells were plated in 6 well-plates with DMEM 10% FBS or RPMI 1640 10% FBS respectively. 24 hours after seeding, the cells were washed with PBS and treated as described in the “Treatment” section, in 1mL medium without FBS. The conditioned medium of MDA-MB-231 and E0771 cells were collected after 24 hours of treatment. MIF levels were measured in the conditioned medium of both cell types, and IL-8 levels were measured only in the conditioned medium of human cells. MIF and IL-8 levels in the conditioned media were measured following the instructions for the Mouse MIF DuoSet (DY1978, R&D Systems, Minneapolis, Minnesota), Human MIF DuoSet (DY289, R&D Systems), and Human IL-8/CXCL8 DuoSet ELISA (DY208, R&D Systems) kits. 2.6 Splenocyte harvesting and culture in conditioned medium Female C57Bl/6 organ donor spleens were harvested and placed in of 12-well plates containing 1 ml of PBS, on ice, in order to isolate the splenocytes. The tissues were crushed using the flat plunger of a 10 ml syringe and, using an 18G needle mounted on a 10 ml syringe, the cells were dissociated by up and down movement to obtain a cell suspension. This cell suspension is then filtered through a 70µm filter and centrifuged at 300g for 10 min at 4 °C. The supernatant is removed, and the cells are resuspended in 5 mL of 1x RBC Lysis Buffer (2701510, Sony Biotechnology Inc., California, USA) and incubated for 5 min at room temperature. 5 mL of PBS is then added to inactivate the lysis. The cells are counted using the Corning ® Cell Counter (Corning, 6749), and viability is analyzed using Trypan Blue. Finally, 3x10 6 cells were deposited in the well of a 6-well plate in 2 mL of conditioned medium from E0771 cells treated for 24 hours with FINs. The splenocytes were incubated overnight at 37 °C, in a 5% CO2 humid atmosphere. The splenocytes were then harvested and prepared for flow cytometry analysis. 2.7 Syngeneic E0771 TNBC model and in vivo treatment with SCD1 inhibitor and anti-PD-1 antibody E0771 cells (5 × 10 5 ) were injected subcutaneously (s.c.) into both flanks of female C57BL/6 mice (6–8 weeks old; Charles River) to establish a syngeneic model of TNBC. The mice were randomly assigned to the different treatment groups before tumor cell injection. Tumor growth was monitored every 2 to 3 days, and tumor volume was calculated using the following formula: (L x l²) x 0.4, L and l represent the tumor length and width, respectively. When tumors reached 70–100 mm³, mice were treated daily by oral gavage with an SCD1 inhibitor T4515, (TargetMol) at 40 mg/kg or with vehicle control (placebo). T4515 was dissolved in DMSO (vehicle) at 40 mg/mL as a stock solution, then diluted in the vehicle formulation and sonicated prior to administration. The final vehicle formulation used for T4515 consisted of 10% DMSO in PBS. In earlier in vivo experiments, the SCD1 inhibitor Abcam #Ab142089 was used and formulated in 2.5% DMSO, 0.5% methylcellulose, and 0.25% Tween 80 in water. For PD-1 blockade, mice received intraperitoneal (i.p.) injections of anti-mouse PD-1 antibody (clone RMP1-14; MedChemExpress, HY-P99144) at 10 mg/kg (0.2 mg per injection per mouse), administered twice weekly on days 1 and 3. Control mice received an IgG isotype control (Rat IgG2a kappa, Isotype Control) (MedChem Express, HY-P990679). For combination therapy (SCD1 inhibitor + anti-PD-1), control (placebo) mice received both corresponding controls (vehicle for SCD1 inhibitor and IgG isotype for anti-PD-1). At the end of the experiment, mice were euthanized by cervical dislocation, and tumors were harvested for flow cytometry and immunohistochemical analysis. Tumors were cut in half, with one half fixed and embedded in paraformaldehyde (PFA) and the other half processed for flow cytometry. All animal procedures were performed in accordance with the guidelines of Federation of European Laboratory Animal Science Associations (FELASA) in an accredited institutional animal facility, and under the approved animal protocol #2458 at the University of Liège, Belgium. 2.8 Immunohistochemistry The half tumors resected from mice were fixed in PFA 10%immediately after resection, dehydrated in ethanol, and embedded in paraffin. The paraffin blocks were cut into 5µm slices for 4-Hydroxynonenal (4-HNE) labeling. The slides were deparaffinized and then autoclaved in citrate buffer. Endogenous peroxidases were blocked with H 2 O 2 , followed by blocking with an animal-free blocking solution (15019, Cell Signaling). The slides were incubated for 1 hour with the primary antibody 4-HNE Antibody (MAB3249, R&D Systems, 1:1000). After rinsing, the slides were incubated for 30 minutes in the Dako EnVision+ System- HRP Labelled Polymer Anti-mouse (Dako K4001). The slides were reveled with SignalStain ® DAB Substrate Kit (#8059, Cell Signaling) for approximately 5 minutes. The slides were counterstained with hematoxylin and mounted with Entellan™ new (1.07961.0100, Sigma-Aldrich). Slides were scanned by Nanozoomer Digital Pathology (NDP) System (Hamammatsu - Shizuoka, Japan). Quantification of 4-HNE immunohistochemistry was performed by QuPath v3.2 (Open-source software for digital pathology image analysis, https://qupath.github.io ) and following the website manual. 2.9 Tumor digestion The two-halve of each tumor were pooled and digested together in a solution conta
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