Immunotherapy holds great promise for cancer treatment. The key to improving the therapeutic effect is to drive the patient's own immune system to produce a strong, effective, and enduring tumor‐specific immune response. Engineered nanoplatforms show promising potential in strengthening antitumor immune responses. However, current nanotherapeutic platforms based on exogenous responses stimulate the immune system only in a transitory and limited manner, which translates into insufficient immune activation and a low therapeutic efficacy. A novel targeted nano‐immunostimulant (ZGS‐Si‐Pc@HA) is fabricated by coupling persistent luminescence nanoparticles with a photosensitizer and hyaluronic acid for sustained immune stimulation upon irradiation with biological window (659 nm) light. ZGS‐Si‐Pc@HA persistently drives reactive oxygen species production to induce immunogenic cell death, causing a durable tumor‐specific immune response. Upon intratumoral injection, ZGS‐Si‐Pc@HA effectively alleviates immune tolerance and promotes T lymphocyte tumor infiltration. Further, ZGS‐Si‐Pc@HA enhances the therapeutic effect of checkpoint blockade immunotherapy, effectively inhibiting bilateral tumor growth and triggering an immunological memory effect. Nano‐immunostimulants not only provide a new way to boost cancer immunotherapy, but also offer a reliable strategy for fighting cancer metastasis and recurrence clinically. Cancer immunotherapy aims to initiate or reinitiate the tumor‐immunity cycle, enabling it to amplify and proliferate, but in a controlled manner. Here, a novel targeted nano‐immunostimulant ZGS‐Si‐Pc@HA, elicits an enduring tumor‐specific immune response for the effective suppression of both primary and distant tumors, and finally induces a durable immune memory effect against tumor rechallenging.
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