Self‐Cooperative Prodrug Nanovesicles Migrate Immune Evasion to Potentiate Chemoradiotherapy in Head and Neck Cancer

Chemoradiotherapy is the standard of care for the clinical treatment of locally advanced head and neck cancers. However, the combination of ion radiation with free chemotherapeutics yields unsatisfactory therapeutic output and severe side effects due to the nonspecific biodistribution of the anticancer drugs. Herein, a self‐cooperative prodrug nanovesicle is reported for highly tumor‐specific chemoradiotherapy. The nanovesicles integrating a prodrug of oxaliplatin (OXA) can passively accumulate at the tumor site and penetrate deep into the tumor mass via matrix metalloproteinase 2‐mediated cleavage of the polyethylene glycol corona. The OXA prodrug can be restored inside the tumor cells with endogenous glutathione to trigger immunogenic cell death (ICD) of the tumor cells and sensitize the tumor to ion radiation. The nanovesicles can be further loaded with the JAK inhibitor ruxolitinib to abolish chemoradiotherapy‐induced programmed death ligand 1 (PD‐L1) upregulation on the surface of the tumor cells, thereby prompting chemoradiotherapy‐induced immunotherapy by blocking the interferon gamma‐Janus kinase‐signal transducer and activator of transcription axis. The prodrug nanoplatform reported herein might present a novel strategy to cooperatively enhance chemoradiotherapy of head and cancer and overcome PD‐L1‐dependent immune evasion.