1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) enhances the therapeutic and immunological efficacy of high-dose radiotherapy in preclinical tumor models

1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) is a synthetic monoacetyldiglyceride known for its immunomodulatory properties, including regulation of pathological neutrophil trafficking and modulation of antitumor immune responses. In this study, we evaluated the therapeutic potential of PLAG as an adjuvant to high-dose radiotherapy using murine tumor models. Combination treatment with PLAG and radiotherapy significantly delayed tumor growth in immunocompetent mice, whereas this therapeutic benefit was absent in immunodeficient hosts, indicating an immune-dependent mechanism. While PLAG selectively enhance CD8⁺ T-cell functional activation when combined with radiotherapy compared to radiotherapy alone, as evidenced by increased numbers of INF-γ⁺, Granzyme B⁺, and effector memory CD8⁺ T-cells. PLAG sustained tumor antigen-specific INF-γ secretion of splenocytes after radiotherapy, indicating prolonged systemic immune activation. Importantly, the amplified systemic immune response translated into a robust abscopal effect. In conclusion, these findings suggest that PLAG amplifies and sustains radiotherapy-induced antitumor immunity by increasing functional activation of CD8⁺ T-cells, and may serve as a promising immunomodulatory adjuvant to improve radiotherapy outcomes.