Nanoparticle-based cancer immunotherapy has shown promising therapeutic potential in clinical settings. However, current research mainly uses nanoparticles as delivery vehicles but overlooks their potential to directly modulate immune responses. Inspired by endogenous endoplasmic reticulum (ER) stress caused by unfolded/misfolded proteins, a rationally designed immunogenic cell death (ICD) inducer named NanoICD is presented. NanoICD is a nanoparticle engineered for ER targeting and retention. By controlling surface composition and properties, NanoICD can effectively accumulate in the ER, induce ER stress, and activate ICD-associated immune responses. NanoICD is generally applicable to various proteins and enzymes, exemplified by encapsulating catalase (CAT) to obtain NanoICD/CAT, which effectively alleviates immunosuppressive tumor microenvironment and induces robust antitumor immune responses in 4T1-bearing mice. The study demonstrates that engineered nanostructures can autonomously regulate biological processes and provides insights into the development of advanced nanomedicines for cancer treatment. NanoICD/BSA was synthesized using a protein nanoencapsulation method, involving in situ-copolymerized neutral monomers, positively charged monomers, ER-targeting ligands, and cross-linkers. The introduction of APm provides a positively charged surface for NanoICD, ensuring effective uptake by cancer cells and escape from lysosomes. The integration of multiple ETLs allows NanoICD to target and tightly bind to the ER after lysosomal escape. By controlling monomer compositions and formulation methodologies, NanoICD efficiently accumulates in the ER, induces ER stress, and activates ICD-associated immune responses. The study also shows that NanoICD/CAT-PCA, which integrates immunomodulating functions by replacing BSA with other functional proteins and enzymes, can effectively alleviate immunosuppressive inflammation and hypoxic TME. The catalytic activity of CAT enables NanoICD/CAT-PCA to decompose H2O2 into O2, alleviating tumor hypoxia and remodeling immunosuppressive TME to enhance cancer immunotherapy. NanoICD/CAT-PCA was shown to significantly improve the survival of 4T1-bearing BALB/c mice, with 50% of tumor-bearing mice alive at 45 days. Histopathological analysis of major organs showed no obvious abnormalities or damage, indicating the safety of NanoICD/CAT-PCA. The study highlights the potential of NanoICD as a platform technology for enhanced cancer immunotherapy. The results suggest that NanoICD can effectively activate T cell-based antitumor immunity and alleviate immunosuppression by the catalytic activity of CAT. The synergy between ICD activation and the remodeling of the immunosuppressive TME contributes to the enhanced antitumor effect. The study provides a novel perspective for the development of advanced nanomedicines for cancer immunotherapy.Nanoparticle-based cancer immunotherapy has shown promising therapeutic potential in clinical settings. However, current research mainly uses nanoparticles as delivery vehicles but overlooks their potential to directly modulate immune responses. Inspired by endogenous endoplasmic reticulum (ER) stress caused by unfolded/misfolded proteins, a rationally designed immunogenic cell death (ICD) inducer named NanoICD is presented. NanoICD is a nanoparticle engineered for ER targeting and retention. By controlling surface composition and properties, NanoICD can effectively accumulate in the ER, induce ER stress, and activate ICD-associated immune responses. NanoICD is generally applicable to various proteins and enzymes, exemplified by encapsulating catalase (CAT) to obtain NanoICD/CAT, which effectively alleviates immunosuppressive tumor microenvironment and induces robust antitumor immune responses in 4T1-bearing mice. The study demonstrates that engineered nanostructures can autonomously regulate biological processes and provides insights into the development of advanced nanomedicines for cancer treatment. NanoICD/BSA was synthesized using a protein nanoencapsulation method, involving in situ-copolymerized neutral monomers, positively charged monomers, ER-targeting ligands, and cross-linkers. The introduction of APm provides a positively charged surface for NanoICD, ensuring effective uptake by cancer cells and escape from lysosomes. The integration of multiple ETLs allows NanoICD to target and tightly bind to the ER after lysosomal escape. By controlling monomer compositions and formulation methodologies, NanoICD efficiently accumulates in the ER, induces ER stress, and activates ICD-associated immune responses. The study also shows that NanoICD/CAT-PCA, which integrates immunomodulating functions by replacing BSA with other functional proteins and enzymes, can effectively alleviate immunosuppressive inflammation and hypoxic TME. The catalytic activity of CAT enables NanoICD/CAT-PCA to decompose H2O2 into O2, alleviating tumor hypoxia and remodeling immunosuppressive TME to enhance cancer immunotherapy. NanoICD/CAT-PCA was shown to significantly improve the survival of 4T1-bearing BALB/c mice, with 50% of tumor-bearing mice alive at 45 days. Histopathological analysis of major organs showed no obvious abnormalities or damage, indicating the safety of NanoICD/CAT-PCA. The study highlights the potential of NanoICD as a platform technology for enhanced cancer immunotherapy. The results suggest that NanoICD can effectively activate T cell-based antitumor immunity and alleviate immunosuppression by the catalytic activity of CAT. The synergy between ICD activation and the remodeling of the immunosuppressive TME contributes to the enhanced antitumor effect. The study provides a novel perspective for the development of advanced nanomedicines for cancer immunotherapy.