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 neutrophil trafficking and enhancement of CD8 ⁺ T-cell responses in both inflammatory and tumor models. 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 without inducing systemic toxicity. Although radiotherapy alone did not increase CD8 ⁺ T-cell infiltration, PLAG enhanced their functional activation when combined with radiotherapy, as indicated by increased numbers of INF-γ ⁺ , Granzyme B ⁺ , and effector memory CD8 ⁺ T-cell subsets. PLAG also sustained tumor antigen-specific INF-γ secretion in splenocytes on day 10 and 15, suggesting prolonged immune activation. This functional reprogramming was associated with a strong systemic antitumor response, including a robust abscopal effect. Immunosuppressive cell populations, such as Treg, M2 macrophages, and MDSCs, remained unchanged, indicating that PLAG likely enhances antitumor immunity by boosting effector CD8 ⁺ T-cell function rather than suppressing regulatory populations. These findings suggest that PLAG amplifies and sustains radiotherapy-induced antitumor immunity and may serve as a promising immunomodulatory adjuvant to improve radiotherapy outcomes.