“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 is 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, nanoparticles loaded with an immune checkpoint inhibitor (JQ‐1) using polypyrrole/hyaluronic acid (PPyHA/JQ‐1) are developed. These nanoparticles offer active tumor targeting, photothermal tumor ablation using near‐infrared light, and laser‐controlled JQ‐1 release for efficient breast cancer treatment. When the molecular weight of HA varies (from 6.8 kDa to 3 MDa) in the PPyHA nanoparticles, it is found that the nanoparticles synthesized using 1 MDa HA, referred to as PPyHA (1 m ), show the most suitable properties, including small hydrodynamic size, high surface HA contents, and colloidal stability. Upon 808 nm laser irradiation, PPyHA/JQ‐1 elevates the temperature above 55 °C, which is sufficient for thermal ablation and active release of JQ‐1 in the tumor microenvironment (TME). Notably, the controlled release of JQ‐1 substantially inhibits the expression of cancer‐promoting genes. Furthermore, PPyHA/JQ‐1 effectively suppresses the expression of programmed cell death ligand 1 (PD‐L1) and prolongs 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, “Three‐in‐one” immunotherapeutic photo‐activable nanoparticles have the potential to be beneficial for a targeted combinatorial treatment approach for TNBC.