Hypofractionated Radiotherapy Induces ISG15 + MHC‐I + Neutrophils to Augment Anti‐Tumor Immunity and Prime Immune Checkpoint Blockade Responses in Rectal Cancer

ABSTRACT Our previous clinical trials had demonstrated that neoadjuvant hypofractionated radiotherapy (HFRT) combined with immunotherapy yields promising clinical outcomes in locally advanced rectal cancer (LARC). However, this combined modality benefits only a subset of patients, highlighting the need to uncover the mechanisms underlying how successful immunotherapy changes the tumor microenvironment to favor tumor control. Here, we showed that HFRT increases ISG15 + MHC‐I + neutrophil infiltration, which exhibits antigen‐presenting capabilities and is crucial for successful neoadjuvant therapy in rectal cancer. Mechanistically, HFRT promotes IFN‐α release, which activates the NOD1/NF‐κB pathway to drive MHC‐I expression in neutrophils. Adoptive transfer of ex vivo‐generated ISG15 + MHC‐I + neutrophils in mouse models enhanced intratumoral CD8 + T cell infiltration, synergizing with anti‐PD‐1 therapy to suppress tumor growth. This study uncovers an HFRT‐induced neutrophil subset that bridges local radiation with systemic immunity, providing a potential strategy to convert “cold” tumors to “hot” phenotypes for enhanced immunotherapy efficacy in microsatellite stability LARC.