Natural‐Inspired Engineered Microalgae With Selenium Enrichment Enabled Potent Anti‐Tumor Immunity

ABSTRACT Immunotherapy has shed light on clinical oncology for several decades. However, it still suffers from heterogeneous therapeutic outcomes and potential immune‐related adverse events (irAEs). Inspired by a natural phenomenon that microalgae can absorb and accumulate selenium (Se), a well‐known healthcare element, we engineered a Se‐enriched cyanobacterium Synechococcus Sp (Se‐ Ssp ) for advanced immunotherapy. Simply by culturing in the presence of Na 2 SeO 3 , Se nanoparticles could be bio‐fabricated within Synechococcus Sp , underscoring a facile preparation process with promising translational potential. With satisfactory biocompatibility and internalization efficiency, Se‐ Ssp boosted dendritic cell maturation and antigen presentation via both the Toll‐like receptor and the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathways, likely attributed to the Se‐enhanced influx of calcium. In vivo studies demonstrated that Se‐ Ssp elicited potent innate immunity and maintained long‐term adaptive immunity, effectively inhibiting tumor growth with sustained protection against recurrence. In addition, Se‐ Ssp was validated to sensitize the reaction of both primary and distant tumors to immune checkpoint and indoleamine 2,3‐dioxygenase inhibitors; it also restrained the progression of orthotopic bladder carcinoma via intravesical instillation as well. Briefly, this study developed an anti‐cancer immune application of engineered Se‐ Ssp , offering a promising alternative with significant therapeutic potential that might benefit patients with cancer.