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Background SECN-15 is a high-affinity antisense oligonucleotide (ASO) designed to selectively downregulate Neuropilin-1 (NRP1). NRP1 is a multifunctional transmembrane co-receptor that promotes tumor progression by suppressing anti-tumor immunity and inducing neoangiogenesis through interactions with receptors such as TGFBR2 and VEGFR2. High NRP1 expression correlates with poor prognosis in multiple solid tumors, including gastric and breast cancer. We evaluated the therapeutic potential of NRP1-targeting ASOs in preclinical models, both as monotherapy and in combination with immune checkpoint inhibitors (ICIs).Methods ASOs targeting NRP1 were designed and characterized using our proprietary OligoCreator™ platform. In vitro efficacy was assessed across different cell lines and primary cells under free uptake conditions. In vivo efficacy was evaluated in syngeneic murine tumor models following systemic administration of ASOs, either as monotherapy or in combination with anti-PD-(L)1 antibodies. Tumors were subjected to bulk and single nuclei RNA sequencing to investigate transcriptomic alterations. Soluble NRP1 levels in serum were measured as a marker of target engagement. Tolerability of systemic NRP1 knockdown was evaluated in a 28-day non-GLP toxicology mouse study. In silico transcriptomic analyses of human cancer datasets were performed to inform indication selection for the planned Phase I/II clinical trial and facilitate translational relevance of the preclinical findings.Results Systemic administration of the SECN-15 mouse surrogate resulted in robust NRP1 knockdown across multiple intra-tumoral cell types, including macrophages and endothelial cells. In the EMT6 breast cancer model, monotherapy induced significant tumor growth delay and achieved complete tumor regression in 20% of treated animals whereas anti-PD-1 monotherapy only had limited activity with no complete regressions. Combination therapy significantly enhanced anti-tumor efficacy leading to complete tumor eradication in ~70% of animals. Transcriptomic profiling revealed upregulation of pro-inflammatory pathways and downregulation of genes involved in epithelial to mesenchymal transition (EMT), a process linked to poor clinical outcomes and resistance to ICI therapy. No adverse effects related to systemic NRP1 downregulation were observed. In silico analyses of human cancer datasets supported the selection of gastric cancer as a lead indication for clinical development and revealed that similar genes and pathways are associated with NRP1 expression in both murine models and human tumors.Conclusions SECN-15 represents a promising new immunotherapeutic strategy to enhance anti-tumor immunity and overcome resistance to checkpoint inhibitors. Our preclinical data demonstrate strong anti-tumor efficacy in the monotherapy, as well as the combination therapy setting. Based on these findings, IND-enabling studies and preparations for first-in-human clinical trials are underway.