A Cascade-Immunomodulating Poly(amino acid)−Metal Coordination Nanoplatform for Enhanced Cancer Immunotherapy

Abstract The limited efficacy of cancer immunotherapy arises not only from insufficient immune activation, but more fundamentally from the absence of a systems-level strategy to coordinate the anti-cancer immunity cycle. Here, a poly(amino acid)−metal coordination nanoplatform comprising methoxy poly(ethylene glycol)−poly(glutamic acid), manganese ion (Mn2+), and quercetin (Quer) is engineered to orchestrate the cancer−immunity cycle dynamically. Mn2+-mediated Fenton-like reaction induces immunogenic cell death and fosters immune-activating tumor microenvironments (TMEs), as supported by a 1.7-fold increase in dendritic cell maturation and a 2.1-fold enhancement in cytotoxic T lymphocytes. Quer remodels the TMEs by reducing collagen deposition and inhibiting the activation of cancer-associated fibroblasts (CAFs), increasing T cell infiltration by 2.8-fold and downregulating programmed death-ligand 1 (PD-L1). Collectively, this platform functions as a coordinated immune cascade that amplifies anti-cancer immunity, achieving a 3.3-fold increase in tumor growth inhibition. This study shifts cancer immunotherapy from static intervention to programmable immune engineering, offering a strategy to overcome therapeutic barriers.