<p>Bladder cancer (BC) remains a prevalent urothelial malignancy characterized by high recurrence and mortality rates, severely compromising patients’ quality of life. Current intravesical chemotherapies, although locally administered, are limited by rapid renal excretion and poor tumor accumulation, which undermines treatment efficacy. Moreover, these conventional agents often cause immunosuppression, further diminishing therapeutic outcomes. To address these challenges, we developed MC/Pep, an innovative amphiphilic peptide-based nanoplatform that self-assembles into spherical nanoparticles capable of codelivering mitoxantrone (MT) and cinnamaldehyde (CA). A key innovative feature of this system is its matrix metalloproteinase 2 (MMP2)-responsive structural transformation, which triggers morphological rearrangement into highly aggregated nanostructures within the tumor microenvironment, enabling enhanced targeted accumulation and retention. In addition to improving drug delivery, MC/Pep induced endoplasmic reticulum oxidative stress-mediated immunogenic cell death (ICD) through the triggering of reactive oxygen species (ROS) generation via intracellular redox reactions. MC/Pep also promoted the production of mitochondria-derived ROS by inducing changes in mitochondrial membrane permeability, thereby synergistically enhancing the ICD effect. This system induced the ectopic displacement of calreticulin (CRT) and the exocytosis of high-mobility group protein B1 (HMGB1) and facilitated DC maturation and T-cell activation in vivo, thereby eliciting an antitumor immune response. Owing to its promising pharmacokinetic properties, tumor-targeting ability, and ability to enhance both immunomodulation and drug accumulation, MC/Pep represents a novel and clinically promising nanotherapeutic strategy for BC, offering a viable path toward translation in immunotherapy-enhanced chemotherapy.</p> Graphical Abstract <p></p>