A Nanoimmunoactivator Induces Endoplasmic Reticulum Stress and Alleviates the Immunosuppression for Synergistic Cancer Immunotherapy

Abstract Cancer immunotherapy has transformed the landscape of cancer treatment. However, the low immunogenicity and immunosuppressive tumor microenvironment (TME) often limit the efficacy of immunotherapy. Activating immune responses while alleviating negative feedback regulation offers a promising strategy to enhance the effectiveness of cancer immunotherapy. Herein, this work proposes a novel nanoparticle‐based immune activator (nanoIA), which can induce immunogenic cell death (ICD) of tumor cells and deliver small‐molecule immunomodulators to further enhance antitumor immune responses. NanoIA features a unique surface structure that enables it to induce ICD by targeting and retaining in the endoplasmic reticulum of tumor cells. Additionally, nanoIA can be loaded with various small‐molecule drugs and released in response to stimuli from the TME. This distinct capability enables nanoIA to initiate and amplify antitumor immune responses. This study employs two small‐molecule immunomodulators, JQ1 and NLG919, as examples for demonstration. NanoIA/JQ1 and nanoIA/NLG919 demonstrated significant efficacy in inhibiting tumor growth, prolonging survival in tumor‐bearing mice, and preventing tumor recurrence and metastasis. These results confirm nanoIA's ability to activate antitumor immune responses and  induce immune memory. This work provides new insights into the development of nanoparticles that actively participate in immune regulation.