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Background Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 therapies, have transformed the treatment of several solid tumors. However, many patients—especially those with prostate, lung, and other immune-cold cancers—either fail to respond or acquire resistance. This resistance is often linked to an immunosuppressive tumor microenvironment (TME), enriched with regulatory T cells (Tregs), exhausted CD8 + T cells, and M2-like macrophages. Recent studies identify dipeptidyl peptidase-4 (DPP4/CD26) as a key contributor to immune evasion through chemokine degradation (e.g., CXCL10) and immunoregulatory expression across suppressive immune subsets. Based on our prior identification of the natural flavonoids chrysin and galangin as DPP4 inhibitors, we propose their investigation as part of a combination strategy with anti-PD-1 therapy to reprogram the TME and overcome ICI resistance.Methods We analyzed publicly available single-cell RNA sequencing data from murine/human prostate and lung tumor models treated with anti-PD-1. Cells were filtered for quality, doublets, and mitochondrial content (>15%). Following normalization and log transformation, 2,000 highly variable genes were selected for PCA. Data integration was performed using Harmony, followed by UMAP for visualization. Cell types were annotated using canonical markers for CD8 + effector T cells, FOXP3+ Tregs, and M1/M2 macrophages. Dpp4 expression was quantified across clusters and compared between responder and non-responder tumors. Gene Set Variation Analysis (GSVA) was used to assess enrichment of immunosuppressive pathways (TGF-β, IL-10), and CellChat analysis inferred ligand-receptor interactions involving DPP4.Results scRNA-seq analysis revealed elevated Dpp4 expression in Tregs, exhausted CD8 + T cells, and M2-like macrophages in non-responding tumors. These DPP4+ subsets were associated with reduced IFN-γ signatures and enrichment of immunosuppressive pathways. Literature evidence supports DPP4’s role in modulating antitumor immunity through chemokine cleavage and M2 polarization. These findings provide a rationale to investigate chrysin and galangin—identified in prior screens as DPP4 inhibitors—as immunomodulatory agents in combination with anti-PD-1 therapy.Conclusions DPP4 emerges as a novel immune checkpoint modulator associated with ICI resistance. Targeting DPP4 using natural small molecules may represent a practical strategy to restore immune responsiveness and enhance checkpoint blockade efficacy in prostate, lung, and other resistant solid tumors.