Breast cancer (BC), comprising for 23 % of female cancers, stands as a prevalent and widespread malignant disease (Loibl et al., 2021, Nolan et al., 2023, Siegel et al., 2023). Despite advancements in chemotherapy, surgery and radiotherapy, these therapeutic approaches have limitations and are generally ineffective, particularly for late-stage patients with BC (Leon-Ferre and Goetz, 2023, Provenzano and Shaaban, 2023). Immune checkpoint inhibitors (ICIs) have garnered significant attention as a promising anticancer therapy by leveraging the immune system’s potential. However, clinical trials have revealed that the sustained response rate to ICIs in most tumor cells of less than 20 %, emphasizing the need to combine ICIs with other modalities (Kawashima and Togashi, 2023, Sharma et al., 2023).

Photothermal therapy (PTT) has garnered attention in recent tumor treatment research as a highly selective and minimally invasive treatment (Xiong et al., 2023). Beyond its direct ablation of cancer cells and tissues, PTT induces immunogenic cell death (ICD) responses, triggering the host immunity (Li et al., 2022). Additionally, the release manner of loaded drugs can be precisely controlled via near-infrared laser irradiation. While combined treatments based on PTT and immunotherapy have been developed (Li et al., 2023a, Li et al., 2023b, Sun et al., 2022), the PTT-induced upregulation of programmed cell death-ligand 1 (PD-L1) and indoleamine 2, 3-dioxygenase 1 (IDO-1) presents a challenge in reducing T cell infiltration and anti-tumor immunity (Wesch et al., 2020, Zhu et al., 2021). Specifically, as an important immunosuppressive molecule, PD-L1-positive tumor cells exhibit relative insensitivity to T cell cytotoxicity, enhancing tumorigenesis and invasiveness. Moreover, tumor cells expressing PD-L1 play intrinsic pro-tumorigenic roles by influencing various biological behaviors, including proliferation, apoptosis and migration (Chen et al., 2016, Gou et al., 2020). IDO-1 functions as a catalytic enzyme by stimulating local tryptophan degradation and depletion, resulting in weakened T-cell functionally and reduced local immunotolerance (Abd El-Fattah, 2022, Fujiwara et al., 2022). Therefore, downregulating PD-L1 and IDO-1 expression activated by PTT emerges as a promising new therapeutic option for BC treatment.

Berberine (BBR), a natural isoquinoline alkaloid with low toxicity derived from the Chinese herb Coptis chinensis Franch, possesses hypoglycemic effects, anti-cancer, anti-diabetic, and anti-bacterial properties (Li et al., 2023a, Li et al., 2023b). Previous studies indicated BBR’s beneficial impact on the tumor immunological microenvironment, reducing PD-L1 levels by blocking CSN5 deubiquitination and inducing AMPK phosphorylation in a dose-dependent manner (Liu et al., 2020, Zheng et al., 2023) and also restoring T cell cytotoxicity (Shah et al., 2022). However, the clinical application of BBR is hindered by poor targeting efficiency, easy metabolic clearance, and low solubility (Zhang et al., 2018). Nanoparticulate drug delivery systems are a promising strategy to improve drug bioavailability and tissue distribution (Cheng et al., 2021), although challenges like low drug loading and burst release persist (Kafle et al., 2022). Previous studies have indicated that BBR can form nanodrugs with various chemotherapy drugs, such as doxorubicin and indomethacin, through intermolecular forces, which could ameliorate the distribution of drugs in the tumors and strengthen the tumor-killing effect (Fu et al., 2022, Zheng et al., 2021).

Thus, we propose that BBR molecules with condensed aromatic structures could engage in self-assembly with specific photothermal agents. Interestingly, indocyanine green (ICG), a near-infrared fluorescent dye composed of polyaromatic polyene groups and sulfonate groups, has been previously observed to co-assemble with BBR molecules in aqueous solutions (Scheme 1). Building on this unique co-assembly property, we developed a near infrared laser (NIR)-responsive, carrier-free drug release system comprising ICG and BBR. Moreover, hyaluronic acid (HA) is utilized to enhance the accumulation of nanocarriers at tumor sites. This study aimed to investigate the physicochemical properties, drug release behavior, and biological properties of the nanodrugs. Additionally, a series of experiments were conducted to investigate the effect of the nanodrugs on the immune microenvironment and assess the feasibility of their combined anti-tumor effect with anti-PD-L1 therapy.