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Background Combining stereotactic ablative radiotherapy (SABR) with immunotherapy has generated significant clinical interest, yet the limited outcomes underscore the need to optimize their synergy. Gold-based therapeutics offer promise for enhancing both radiotherapy and immunotherapy, but their clinical translation is hindered by poor in vivo clearance and associated toxicity. Galectin-1 (Gal-1) is overexpressed in a wide range of malignant cancers and is strongly associated with immune suppression as well as cancer aggressiveness. However, effective therapeutics targeting Galectin-1 remain elusive in clinical practice. To address these challenges, we developed biodegradable gold supraclusters (BSCgal) that enable concurrent radiosensitization and silencing of the immunosuppressive checkpoint protein Gal-1 to enhance combinational radio-immunotherapy.Methods BSCgal consists of cationic gold nanoclusters reversibly crosslinked with siRNA and embedded in a slowly degrading polymer matrix ( figure 1). This design enables sustained activity and efficient clearance—achieving 90.3% clearance in vivo within 4 weeks following systemic injection, resulting in minimized long-term toxicity. The supraclusters before degradation are sized above the renal filtration threshold, supporting passive tumor accumulation. Following mice studies, we have also investigated the efficiency of BSCgal under a clinical linear accelerator (LINAC) and explored the capability of BSCgal to treat canine head and neck cancer (HNC).Results In mouse models of HNC, BSCgal enhances both radiodynamic and immune responses of SABR. It increases infiltration of tumor-inhibitory leukocytes, elevates cytotoxic granzyme B expression, and reduces immunosuppressive myeloid-derived suppressor cells (MDSCs). Its therapeutic outcomes in combination with SABR outperform those of SABR combined with Gal-1 antagonists (e.g. small molecule inhibitor or antibody), cisplatin, or PD-1 inhibitors. It also enhances the abscopal effects of SABR and promotes the inhibition of distant metastases that are difficult to target by radiation. Furthermore, it can radiosensitize megavoltage RT from LINAC and inhibit cancer cell proliferation, showing excellent therapeutic potential for treating canine HNC with Gal-1 overexpression.Conclusions Our findings demonstrate a clinically relevant strategy to integrate localized radiosensitization with targeted immune modulation. The strong interactions between supraclusters and antigen-presenting cells can be leveraged to co-deliver mRNA for vaccine development. The inherent imaging capability of supraclusters also enables real-time tracking in vivo. Evaluating BSCgal in pet dogs with HNC will facilitate its transition to human clinical trials. Overall, this research accelerates the clinical translation of gold therapeutics and establishes a versatile platform that synergizes localized radiosensitization with targeted immune checkpoint silencing, contributing to the advancement of personalized radioimmunotherapy.Abstract 671 Figure 1