Tumor inflammation-specific self-amplifying fluorescent molecular probes induce an anti-tumor immune response

Abstract

Enhancing the concentration of exogenous molecular drugs within the tumor microenvironment through enzyme-catalyzed polymerization presents a novel strategy for cancer therapy. Nonetheless, the optimization of the catalytic efficiency is often impeded by the inefficient expression of enzymes. Herein, we reported a self-amplifying fluorescent molecular probe, Bis-HTP-ICG, for photodynamic therapy (PDT) and subsequent PDT-induced immunoreaction. The Bis-HTP-ICG probe possesses a noticeable enzyme-catalyzed polymerization facilitated by myeloperoxidase (MPO), a crucial enzyme secreted by neutrophils at inflammation sites. Upon exposure to laser irradiation, Bis-HTP-ICG showed a high PDT efficacy, inducing an acute inflammatory response that stimulates further recruitment of neutrophils and then elevated MPO secretion. The heightened level of MPO enhances the accumulation of the Bis-HTP-ICG via self-polymerization or binding with intratumoral proteins following MPO enzyme catalysis, instigating a self-amplifying chain reaction cycle involving Bis-HTP-ICG, neutrophils and MPO. Meanwhile, PDT efficiently incites immunogenic cell death (ICD) in tumor cells, initiating an anti-tumor immune response including dendritic cells (DCs) maturation, T cell proliferation and reprogramming of tumor-associated neutrophils (TANs). This work portrays a promising strategy for self-amplification of fluorescent molecular probes through adjustable enzyme levels, potentially offering a unique avenue to enhance the tumor accumulation of molecular drugs for improved tumor therapy.