Manipulating the Crosstalk between Cancer and Immunosuppressive Cells with Phototherapeutic Gold‐Nanohut for Reprogramming Tumor Microenvironment

Abstract Photoimmunotherapy faces challenges due to insufficient intratumoral accumulation of photothermal agents and the reversion of the cancer‐immunity cycle during treatment. In this study, an anti‐PD‐L1‐immobilized magnetic gold nanohut, AuNH‐2‐Ab, with photoresponsive, thermosensitive, and immunomodulatory properties to effectively suppress the growth of primary tumors, elevate immunogenic cell death (ICD) levels, reverse the tumor immune microenvironment (TIME), and consequently inhibit metastases are developed. AuNH‐2‐Ab achieves high tumor accumulation (9.54% injected dose) following systemic administration, allowing the modulation of hyperthermia dose of over 50 °C in the tumor. By optimizing the hyperthermia dose, AuNH‐2‐Ab simultaneously target and eliminate cancer cells and tumor‐associated macrophages, thereby activating potent antitumor immunity without being compromised by immunosuppressive elements. Hyperthermia/pH induced morphological transformation of AuNH‐2‐Ab involving the detachment of the surface antibody for in situ PD‐L1 inhibition, and exposure of the inner fucoidan layer for natural killer (NK) cell activation. This precision photoimmunotherapy approach reprograms the TIME, significantly prolongs survival in a murine hepatocellular carcinoma model (Hep55.1c), and harnesses the synergistic effects of ICD production and checkpoint inhibitors by utilizing a single nanoplatform.