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Caerin 1.1/1.9 peptides cooperate with 5- uorouracil to suppress melanoma by reprogramming myeloid suppressor cells and regulatory T cells
Preprint   Open access

Caerin 1.1/1.9 peptides cooperate with 5- uorouracil to suppress melanoma by reprogramming myeloid suppressor cells and regulatory T cells

Xinyi Song, Jiawei Fu, Quanlan Fu, Junjie Li, Yuandong Luo, Hejie Li, Xiao Song Liu, Guoying Ni and Tianfang Wang
Research Square, Vol.4 February 2026
Research Square Company
2026
DOI: https://doi.org/10.21203/rs.3.rs-8780310/v1
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Preprint VersionCC BY V4.0,  Open Access

Abstract

Melanoma 5-Fluorouracil Caerin peptide B16 cell Regulatory T cell Myeloid-derived suppressor cell Single-cell RNA sequencing
Purpose Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are major barriers to effective anti-tumour immunity in melanoma. While 5-fluorouracil (5-FU) can partially modulate tumour immunity, its effects are often incomplete. We investigated whether combining host-defence peptides caerin 1.1/1.9 (F1/F3) with 5-FU enhances antitumour efficacy by reprogramming immunosuppressive compartments within the tumour microenvironment (TME). Experimental Design: Antitumour activity of F1/F3 and 5-FU was assessed in the B16 melanoma model using survival, tumour burden, and immune profiling analyses. Cytotoxic interactions were evaluated in vitro. Flow cytometry, single-cell RNA sequencing, T-cell receptor repertoire analysis, cytokine assays, and bioinformatic approaches characterised immune composition, functional states, and intercellular communication under different treatments. Results F1/F3 and 5-FU did not exhibit synergistic cytotoxicity in vitro but produced marked therapeutic synergy in vivo. Dual therapy (DT) significantly prolonged survival and enhanced intratumoural CD8⁺ T-cell infiltration while reducing immunosuppressive MDSCs and Tregs. scRNA-seq revealed that DT selectively impaired metabolically active neutrophil-like PMN-MDSCs and reprogrammed monocytic M-MDSCs toward an IL-1/NF-κB–driven inflammatory, immune-interactive state. Tregs under DT showed destabilisation of canonical suppressive programs and acquisition of effector-like features. These changes were accompanied by enhanced myeloid–lymphoid communication and pronounced clonal focusing of tumour-infiltrating T cells, indicating antigen-driven immune activation. Conclusions F1/F3 peptides convert 5-FU from a partially immunomodulatory chemotherapy into a potent immune-reprogramming regimen by dismantling myeloid and Treg-mediated suppression. This coordinated remodelling of the TME promotes effective adaptive immunity and provides a mechanistic rationale for integrating host-defence peptides with chemotherapy to overcome immune resistance in melanoma.

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