rSiglec-10(V set) armed oncolytic adenovirus improves the effects of virotherapy through enhancing oncolysis and antitumor immunity.

The CD24-Siglec-10 interaction is recognized as an important component of the immunosuppressive network in tumors. CD24, which is highly expressed on tumor cells, promotes immune evasion through binding to Siglec-10 on immune cells. Therefore, targeting the CD24-Siglec-10 axis represents a promising therapeutic strategy. In this study, we genetically engineered an oncolytic adenovirus to express a novel recombinant protein consisting of the Ig-like V-type domain of mouse Siglec-10 and the Fc fragment of mouse IgG2a (termed as rSiglec-10(V set)), aiming to disrupt CD24-Siglec-10 interaction and enhance virotherapy. Our results demonstrated that OVs-rSiglec-10(V set) exhibited superior efficacy and prolonged survival in the immunotherapy-resistant 4T1 triple-negative breast cancer. In the A20 lymphoma model, treatment induced complete tumor regression in a subset of mice. Notably, these therapeutic effects were more pronounced in tumors with high CD24 expression. Mechanistically, rSiglec-10(V set) effectively bound to CD24 and enhanced viral replication by activating the Src-ERK pathway, thereby promoting oncolysis. These findings suggest a previously underappreciated link between CD24 targeting and enhanced OV replication. From an immunological perspective, OVs-rSiglec-10(V set) reshaped the TME by increasing CD8+ T cell infiltration and upregulating cytokines associated with T cell chemotaxis and function. Moreover, OV treatment upregulated PD-L1 expression in TME, and combination therapy with anti-PD-L1 further enhanced T-cell infiltration and antitumor immunity. This study provides a novel strategy to improve the therapeutic efficacy of oncolytic virotherapy.