ROS Cascade‐Amplified Polymeric Nanosystem Exhibiting Multi‐Pathway Induction of Immunogenic Cell Death and Chemotherapeutic Efficacy in Tumor

Immunotherapy and chemotherapy for tumors still confront significant obstacles, which call for the creation of new potent treatment approaches. One promising strategy to improve anticancer immune responses is to induce immunogenic cell death (ICD) in tumor cells. However, currently available ICD-inducing agents are limited by several factors, including homogeneous mechanisms of action, low induction efficiency, and complex preparation or administration procedures. To improve ICD induction, particularly in immunologically "cold" tumors, this study proposes a drug co-delivery system designed to achieve effective chemotherapy and multi-pathway ICD induction, thereby enhancing antitumor immunity and improving the efficacy of chemoimmunotherapy. Specifically, a poly(podophyllotoxin)-based polymer was engineered to encapsulate the carbon monoxide (CO) prodrug COP, followed by surface modification with D-α-tocopheryl polyethylene glycol succinate, a stabilizing agent that promotes reactive oxygen species (ROS) generation. This design yielded a ROS cascade-amplified drug delivery platform for chemoimmunotherapy. Damage-associated molecular patterns (DAMPs) were released when ROS, CO, and podophyllotoxin combined to trigger ICD in cancer cells. Subsequently, these DAMPs facilitated the activation and maturation of dendritic cells, which then attracted cytotoxic T lymphocytes, thereby amplifying antitumor immune responses and improving treatment results.