Breast cancer is the most frequent malignancy affecting women, yet current therapeutic strategies remain ineffective for patients with late‐stage or metastatic disease. Here an effective strategy is reported for treating metastatic breast cancer. Specifically, a self‐assembling dendrimer nanosystem decorated with an antibody against programmed cell death ligand 1 (PD‐L1) is established for delivering a small interfering RNA (siRNA) to target 3‐phosphoinositide‐dependent protein kinase‐1 (PDK1), a kinase involved in cancer metabolism and metastasis. This nanosystem, named PPD, is designed to target PD‐L1 for cancer‐specific delivery of the siRNA to inhibit PDK1 and modulate cancer metabolism while promoting programmed cell death 1 (PD‐1)/PD‐L1 pathway‐based immunotherapy. Indeed, PPD effectively generates simultaneous inhibition of PDK1‐induced glycolysis and the PD‐1/PD‐L1 pathway‐related immune response, leading to potent inhibition of tumor growth and metastasis without any notable toxicity in tumor‐bearing mouse models. Collectively, these results highlight the potential use of PPD as an effective and safe tumor‐targeting therapy for breast cancer. This study constitutes a successful proof of principle exploiting the intrinsic features of the tumor microenvironment and metabolism alongside a unique self‐assembling dendrimer platform to achieve specific tumor targeting and siRNA‐based gene silencing in combined and precision cancer therapy.

Bladder cancer is one of the most commonly diagnosed cancers worldwide, especially in males. Current therapeutic interventions, including surgery, radiation therapy, chemotherapy, and immunotherapy, have not been able to improve the clinical outcome of bladder cancer patients with satisfaction. Recombinant human arginase (rhArg, BCT‐100) is a novel agent with great anticancer effects on arginine‐auxotrophic tumors. However, the effects of BCT‐100 on bladder cancer remain unclear. In this study, the in vitro anticancer effects of BCT‐100 were assessed using four bladder cancer cell lines (J82, SCaBER, T24, and 5637), while the in vivo effects were evaluated by establishing T24 nude mice xenograft models. Intracellular arginine level was observed to be sharply decreased followed by the onset of apoptotic events. Furthermore, BCT‐100 was found to induce H₂O₂ production and mitochondrial membrane depolarization, leading to the release of mitochondrial cytochrome c and Smac to the cytosol. Treatment with BCT was observed to upregulate the expression of LC3B and Becllin‐1, but downregulate the expression of p62 in a time‐dependent manner. Autophagic flux was also observed upon BCT‐100 treatment. Besides, the phosphorylation of the AKT/mTOR pathway was suppressed in a time‐dependent fashion in BCT‐100‐treated T24 cells. While N‐acetyl‐L‐cysteine was shown to alleviate BCT‐100‐induced apoptosis and autophagy, chloroquine, MK‐2206, and rapamycin were found to potentiate BCT‐100‐triggered apoptosis. Finally, BCT‐100 was demonstrated to induce autophagy and apoptosis via the ROS‐mediated AKT/mTOR signaling pathway in bladder cancer cells.