Biomimetic Nano‐Immunoactivator via Ionic Metabolic Modulation for Strengthened NIR‐II Photothermal Immunotherapy

Abstract Reprogramming the immunologically “cold” environment of solid tumors is currently becoming the mainstream strategy to elicit powerful and systemic anticancer immunity. Here, a facile and biomimetic nano‐immunnoactivator (CuS/Z@M_4T1) is detailed by engineering a Zn²⁺‐bonded zeolitic imidazolate framework‐8 (ZIF‐8) with CuS nanodots (NDs) and cancer cell membrane for amplified near‐infrared‐II (NIR‐II) photothermal immunotherapy via Zn²⁺ metabolic modulation. Taking advantage of the NIR‐II photothermal effect of CuS NDs and the acidic responsiveness of ZIF‐8, CuS/Z@M_4T1 rapidly causes intracellular Zn²⁺ pool overload and disturbs the metabolic flux of 4T1 cells, which effectively hamper the production of heat shock proteins and relieve the resistance of photothermal therapy (PTT). Thus, amplified immunogenic cell death is evoked and initiates the immune cascade both in vivo and in vitro as demonstrated by dendritic cells maturation and T‐cell infiltration. Further combination with antiprogrammed death 1 (aPD‐1) achieves escalated antitumor efficacy which eliminates the primary, distant tumor and avidly inhibits lung metastasis due to cooperation of enhanced photothermal stimulation and empowerment of cytotoxic T lymphocytes by aPD‐1. Collectively, this work provides the first report of using the intrinsic modulation property of meta‐organometallic ZIF‐8 for enhanced cancer photoimmunotherapy together with aPD‐1, thereby inspiring a novel combined paradigm of ion‐rich nanomaterials for cancer treatment.