The article presents a novel nanoparticle-based approach for cancer immunotherapy, focusing on the design of immunogenic cell death (ICD) inducers. The researchers developed a nanoparticle named NanoICD, which is engineered to target and retain in the endoplasmic reticulum (ER) to induce ER stress and activate ICD-associated immune responses. By controlling the surface composition and properties, NanoICD effectively accumulates in the ER, induces ER stress, and activates immune responses. The study demonstrates that NanoICD can be tailored to enhance its immunomodulatory capacity by encapsulating different proteins and enzymes, such as catalase (CAT), which decomposes hydrogen peroxide (H2O2) to alleviate tumor hypoxia and immunosuppression. In vivo experiments in 4T1-bearing mice showed that NanoICD/CAT-PCA, a version of NanoICD coated with a pH-responsive polymer, significantly suppressed tumor growth, improved survival, and reduced metastasis. This work highlights the potential of engineered nanoparticles to autonomously regulate biological processes and provides insights into the development of advanced nanomedicines for cancer treatment.The article presents a novel nanoparticle-based approach for cancer immunotherapy, focusing on the design of immunogenic cell death (ICD) inducers. The researchers developed a nanoparticle named NanoICD, which is engineered to target and retain in the endoplasmic reticulum (ER) to induce ER stress and activate ICD-associated immune responses. By controlling the surface composition and properties, NanoICD effectively accumulates in the ER, induces ER stress, and activates immune responses. The study demonstrates that NanoICD can be tailored to enhance its immunomodulatory capacity by encapsulating different proteins and enzymes, such as catalase (CAT), which decomposes hydrogen peroxide (H2O2) to alleviate tumor hypoxia and immunosuppression. In vivo experiments in 4T1-bearing mice showed that NanoICD/CAT-PCA, a version of NanoICD coated with a pH-responsive polymer, significantly suppressed tumor growth, improved survival, and reduced metastasis. This work highlights the potential of engineered nanoparticles to autonomously regulate biological processes and provides insights into the development of advanced nanomedicines for cancer treatment.