Multi‐Functional AIE Phototheranostic Agent Enhancing αPD‐L1 Response for Oral Squamous Cell Carcinoma Immunotherapy

Abstract Oral squamous cell carcinoma (OSCC) represents a prevalent head and neck malignancy with surgical intervention as the primary clinical option. Immunotherapy, particularly immune checkpoint blockade (ICB) targeting PD‐1/PD‐L1 shows great promise but is impeded by the immunosuppressive tumor microenvironment and low PD‐L1 expression in OSCC. Herein, the “all‐in‐one” phototherapeutic nanoparticles (TSD NPs) are reported with balanced reactive oxygen species and photothermal conversion capacity for combined photoimmunotherapy and ICB immunotherapy against OSCC. A novel electron acceptor, 3‐(dicyanomethylene)‐2,3‐dihydrobenzothiophene‐1,1‐dioxide (DTM), is introduced to develop the phototherapeutic agent with aggregation‐induced emission (AIE) feature and NIR‐II fluorescence centered at 1000 nm. Benefiting from the AIE feature and the DTM acceptor, the resultant TSD NPs also exhibit strong type I reactive oxygen species (ROS) generation and high photothermal conversion efficiency (45.3%), which can profoundly induce immunogenic cell death (ICD), activate cytotoxic T lymphocytes, and convert the immunosuppressive tumor microenvironment into an immune‐supportive one. Additionally, TSD NPs upregulate the PD‐L1 expression on OSCC cells, thus enhancing the efficacy of combined treatment with α PD‐L1 ICB immunotherapy. This results show that the synergistic treatment of TSD NPs and α PD‐L1 effectively eradicates solid OSCC tumors without adverse effects on normal tissues, proving a novel and promising strategy for OSCC management.