Reprogramming Tumor‐Associated Neutrophils to Enhance Radio‐Immunotherapy

ABSTRACT As central effector cells in innate immunity, neutrophils are rapidly recruited to tumors following radiotherapy (RT). However, their frequent polarization toward the pro‐tumor N2 phenotype and the formation of metastasis‐promoting neutrophil extracellular traps (NETs) significantly limit treatment outcomes. To reprogram these RT‐recruited tumor‐associated neutrophils (TANs), we develop injectable hydrogel microspheres (HMPs) co‐loaded with a TLR4 agonist (lipopolysaccharide) and a PAD4 inhibitor (GSK484). The resulting L/G@HMPs effectively redirect TAN polarization toward the anti‐tumor N1 phenotype, inhibit NET formation, and extend neutrophil lifespan beyond 72 h. In murine tumor models, the combination of RT and L/G@HMPs triggers robust innate and adaptive immune responses, marked by substantial accumulation of N1‐polarized TANs and CD8 + T cells within tumors, leading to potent tumor eradication. This study presents a hydrogel‐based strategy that concurrently modulates neutrophil lifespan, phenotype, and NETs, thereby transforming tumor‐promoting neutrophils into anti‐tumor allies for enhanced radio‐immunotherapy.