Second near-infrared light-activated semiconducting polymer nanomediators enable three-in-one tumor microenvironment modulation for combination immunotherapy

Although various nanoplatforms have been developed for treating cancer, their therapeutic benefits are often greatly limited due to the pathophysiologic tumor microenvironment. Herein, we develop second near-infrared (NIR-II) light-activated semiconducting polymer nanomediators that enable modulation of tumor microenvironment via a three-in-one strategy for combination immunotherapy. Such nanomediators are designed to contain an inside core with encapsulations of NIR-II absorbing semiconducting polymer nanoparticles (SPNs), an inhibitor of programmed death-ligand 1 (PD-L1), and a nitric oxide (NO) precursor, and a thermal-responsive shell with modification of bromelain. The releases of NO precursor and PD-L1 inhibitors in tumor sites are activated by NIR-II laser irradiation due to the destruction of thermal-responsive shell via SPNs-mediated NIR-II photothermal therapy (PTT). After NIR-II light-activation, these nanomediators enable (i) degradation of tumor extracellular matrix by surface modified bromelain to improve the nanoparticle accumulation and immune cell infiltration into tumor sites, (ii) enhancement of tumor immunogenicity via immunogenic cell death effect of NIR-II PTT and NO-based gas therapy, and (iii) reversal of PD-L1 immunosuppressive microenvironment. This three-in-one tumor microenvironment modulation strategy thus enables an amplified antitumor immune response to treat bilateral mouse breast carcinoma. This study provides a versatile platform for the effective and specific treatment of cancer.