Reprogramming immunosuppressive TMEs with Salmonella-delivered sialidase and COX-2 blockade synergistically enhances cancer immunotherapy.

Sialic acid is a component of the extracellular matrix that is upregulated in multiple tumors and plays critical roles in tumorigenesis and progression. Sialic acid engages sialic acid-binding immunoglobulin-like lectins (Siglecs) on immune cells to suppress immune activation. Despite the potential of sialylation-targeted therapies to reactivate antitumor immunity, their clinical translation remains limited by suboptimal drug delivery systems and insufficient tumor specificity. To overcome these obstacles, we engineered a sialidase-expressing S. typhimurium and termed it SLpnanH. The engineered avirulent bacteria can express and secrete sialidase in situ upon L-arabinose induction. In highly immunosuppressive tumor microenvironments, SLpnanH manifests very specific tumor-targeting capabilities and expresses sialidase at high levels. This study demonstrates that engineered SLpnanH significantly mitigates the tumor immunosuppressive microenvironment and inhibits tumor growth with markedly elongated animal survival compared with control groups. Furthermore, treatment with SLpnanH promotes the infiltration and activation of CD8+ T cells and dendritic cells (DCs) in the tumor-draining lymph nodes. When combined with a selective cyclooxygenase-2 (COX-2) inhibitor, the therapeutic efficacy of SLpnanH was further enhanced. Collectively, these findings underscore SLpnanH as a promising candidate for cancer immunotherapy, with its antitumor efficacy significantly augmented by the adjunctive application of an FDA-approved COX-2 inhibitor.