The C/EBPβ antagonist peptide lucicebtide (ST101) induces macrophage polarization toward a pro-inflammatory phenotype and enhances anti-tumor immune responses
Immune-checkpoint inhibitors (ICIs) have shown unprecedented success in a subset of immunogenic tumors, however a host of patients with advanced solid tumors fail to respond well or at all to immunotherapy. Refractory tumors commonly display a tumor microenvironment (TME) rich in immunosuppressive m...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2025-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1522699/full |
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| author | Claudio Scuoppo Rick Ramirez Siok F. Leong Mark Koester Zachary F. Mattes Karen Mendelson Julia Diehl Franco Abbate Erin Gallagher Lila Ghamsari Abi Vainstein-Haras Gene Merutka Barry J. Kappel Jim A. Rotolo |
| author_facet | Claudio Scuoppo Rick Ramirez Siok F. Leong Mark Koester Zachary F. Mattes Karen Mendelson Julia Diehl Franco Abbate Erin Gallagher Lila Ghamsari Abi Vainstein-Haras Gene Merutka Barry J. Kappel Jim A. Rotolo |
| author_sort | Claudio Scuoppo |
| collection | DOAJ |
| description | Immune-checkpoint inhibitors (ICIs) have shown unprecedented success in a subset of immunogenic tumors, however a host of patients with advanced solid tumors fail to respond well or at all to immunotherapy. Refractory tumors commonly display a tumor microenvironment (TME) rich in immunosuppressive macrophages (M2-like) that suppress adaptive immunity and promote tumor progression. The ability to reprogram macrophages in the TME into an immune-active state holds great promise for enhancing responses to ICIs. Lucicebtide (previously referred to as ST101) is a peptide antagonist of the transcription factor C/EBPβ, a key activator of the transcriptional program in immunosuppressive macrophages. Here we show that lucicebtide exposure reprograms human immunosuppressive M2-like macrophages to a pro-inflammatory M1-like phenotype, restores cytotoxic T cell activation in immunosuppressed co-culture assays in vitro, and further increases T-cell activity in M1-like/T cell co-cultures. In immunocompetent, macrophage-rich triple-negative breast and colorectal cancer models, lucicebtide induces repolarization of tumor-associated macrophages (TAMs) to a pro-inflammatory M1-like phenotype and suppresses tumor growth. Lucicebtide synergizes with anti-PD-1 therapy and overcomes resistance to checkpoint inhibition in anti-PD-1-refractory tumors, but in vivo responses are impaired by systemic macrophage depletion, indicating that macrophage reprogramming is integral to lucicebtide activity. These results identify lucicebtide as a novel immunomodulator that reprograms immunosuppressive macrophage populations to enhance anti-tumor activity and suggests its utility for combination strategies in cancers with poor response to ICIs. |
| format | Article |
| id | doaj-art-9a7a54708a7d4878a64b8e8b0156a89e |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-9a7a54708a7d4878a64b8e8b0156a89e2025-08-20T02:46:28ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-03-011610.3389/fimmu.2025.15226991522699The C/EBPβ antagonist peptide lucicebtide (ST101) induces macrophage polarization toward a pro-inflammatory phenotype and enhances anti-tumor immune responsesClaudio ScuoppoRick RamirezSiok F. LeongMark KoesterZachary F. MattesKaren MendelsonJulia DiehlFranco AbbateErin GallagherLila GhamsariAbi Vainstein-HarasGene MerutkaBarry J. KappelJim A. RotoloImmune-checkpoint inhibitors (ICIs) have shown unprecedented success in a subset of immunogenic tumors, however a host of patients with advanced solid tumors fail to respond well or at all to immunotherapy. Refractory tumors commonly display a tumor microenvironment (TME) rich in immunosuppressive macrophages (M2-like) that suppress adaptive immunity and promote tumor progression. The ability to reprogram macrophages in the TME into an immune-active state holds great promise for enhancing responses to ICIs. Lucicebtide (previously referred to as ST101) is a peptide antagonist of the transcription factor C/EBPβ, a key activator of the transcriptional program in immunosuppressive macrophages. Here we show that lucicebtide exposure reprograms human immunosuppressive M2-like macrophages to a pro-inflammatory M1-like phenotype, restores cytotoxic T cell activation in immunosuppressed co-culture assays in vitro, and further increases T-cell activity in M1-like/T cell co-cultures. In immunocompetent, macrophage-rich triple-negative breast and colorectal cancer models, lucicebtide induces repolarization of tumor-associated macrophages (TAMs) to a pro-inflammatory M1-like phenotype and suppresses tumor growth. Lucicebtide synergizes with anti-PD-1 therapy and overcomes resistance to checkpoint inhibition in anti-PD-1-refractory tumors, but in vivo responses are impaired by systemic macrophage depletion, indicating that macrophage reprogramming is integral to lucicebtide activity. These results identify lucicebtide as a novel immunomodulator that reprograms immunosuppressive macrophage populations to enhance anti-tumor activity and suggests its utility for combination strategies in cancers with poor response to ICIs.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1522699/fullC/EBPβlucicebtidetumor associate macrophages (TAM)M2-type macrophageanti-pd 1 immunotherapyST101 |
| spellingShingle | Claudio Scuoppo Rick Ramirez Siok F. Leong Mark Koester Zachary F. Mattes Karen Mendelson Julia Diehl Franco Abbate Erin Gallagher Lila Ghamsari Abi Vainstein-Haras Gene Merutka Barry J. Kappel Jim A. Rotolo The C/EBPβ antagonist peptide lucicebtide (ST101) induces macrophage polarization toward a pro-inflammatory phenotype and enhances anti-tumor immune responses Frontiers in Immunology C/EBPβ lucicebtide tumor associate macrophages (TAM) M2-type macrophage anti-pd 1 immunotherapy ST101 |
| title | The C/EBPβ antagonist peptide lucicebtide (ST101) induces macrophage polarization toward a pro-inflammatory phenotype and enhances anti-tumor immune responses |
| title_full | The C/EBPβ antagonist peptide lucicebtide (ST101) induces macrophage polarization toward a pro-inflammatory phenotype and enhances anti-tumor immune responses |
| title_fullStr | The C/EBPβ antagonist peptide lucicebtide (ST101) induces macrophage polarization toward a pro-inflammatory phenotype and enhances anti-tumor immune responses |
| title_full_unstemmed | The C/EBPβ antagonist peptide lucicebtide (ST101) induces macrophage polarization toward a pro-inflammatory phenotype and enhances anti-tumor immune responses |
| title_short | The C/EBPβ antagonist peptide lucicebtide (ST101) induces macrophage polarization toward a pro-inflammatory phenotype and enhances anti-tumor immune responses |
| title_sort | c ebpβ antagonist peptide lucicebtide st101 induces macrophage polarization toward a pro inflammatory phenotype and enhances anti tumor immune responses |
| topic | C/EBPβ lucicebtide tumor associate macrophages (TAM) M2-type macrophage anti-pd 1 immunotherapy ST101 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1522699/full |
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