“Three‐in‐one”: A Photoactivable Nanoplatform Evokes Anti‐Immune Response by Inhibiting BRD4‐cMYC‐PDL1 Axis to Intensify Photo‐Immunotherapy.

Abstract Combinatorial immuno‐cancer therapy has been recognized as a promising approach for efficiently treating malignant tumors. Yet, the development of multifunctional nanomedicine capable of precise tumor targeting, remote activation, and immune‐regulating drug delivery remains a significant challenge. In this study, we developed nanoparticles loaded with an immune checkpoint inhibitor (JQ‐1) using polypyrrole/hyaluronic acid (PPyHA/JQ‐1). These nanoparticles offer active tumor targeting, photothermal tumor ablation using near‐infrared light, and laser‐controlled JQ‐1 release for efficient breast cancer treatment. We varied the molecular weights of HA (6.8 kDa to 3 MDa) in the PPyHA nanoparticles and found that the nanoparticles synthesized using 1 MDa HA, referred to as PPyHA (1 M), showed the most suitable properties, including small hydrodynamic size, high surface HA contents, and colloidal stability. Upon 808‐nm laser irradiation, PPyHA/JQ‐1 elevated the temperature above 55 °C, which was sufficient for thermal ablation and active release of JQ‐1 in the tumor microenvironment (TME). Notably, the controlled release of JQ‐1 substantially inhibited the expression of cancer‐promoting c‐MYC/BRD4 genes. Furthermore, PPyHA/JQ‐1 effectively suppressed the expression of programmed cell death ligand 1 (PD‐L1) and prolonged dendritic cell maturation and CD8+ T cell activation against the tumor both in vitro and in vivo. PPyHA/JQ‐1 treatment simultaneously provides a significant tumor regression through photothermal therapy and immune checkpoint blockade, leading to a durable antitumor‐immune response. Overall, our “Three‐in‐one” immunotherapeutic photo‐activable nanoparticles have the potential to be beneficial for a targeted combinatorial treatment approach for TNBC. This article is protected by copyright. All rights reserved