2136 - RADA32-LTX315-Simvastatin Hydrogel (RLS) and Radiotherapy Efficacy in Glioblastoma

Purpose/Objective(s):

To evaluate a novel self-assembling hydrogel system (RLS), combining oncolytic peptide LTX315, RADA32 scaffold, and simvastatin, for radiotherapy and immune modulation in GBM.

Materials/Methods:

1. In vitro/in vivo efficacy: Assessed direct cytotoxicity of RLS against GBM cells and its synergy with radiotherapy.
2. Immune modulation: Analyzed M1/M2 macrophage polarization, CD8+ T cell activation (IFN-? secretion), and microglial infiltration via flow cytometry/IHC.
3. Mechanistic studies: Investigated PD-L1 degradation through SQSTM1-dependent autophagy and reversal of radiation-induced PD-L1 upregulation.
4. Safety: Evaluated biocompatibility in murine models.

Results:

• RLS exhibited potent antitumor activity and significantly enhanced sensitivity to radiotherapy.
• Induced M2-to-M1 macrophage polarization, increased CD8+ T cell IFN-? production, and promoted microglia/macrophage tumor infiltration.
• Degraded PD-L1 via autophagy, counteracting radiation-induced PD-L1 upregulation, thereby reducing immune evasion.
• In orthotopic GBM models, RLS combined with standard therapy prolonged recurrence-free survival without systemic toxicity.

Conclusion:

The RLS hydrogel synergizes with radiotherapy by dual-targeting tumor cells and the immunosuppressive niche, offering a translatable strategy to improve GBM outcomes. Its safety profile supports clinical development.