Harnessing sulfur-doped carbon nanodots conjugated with IDO inhibitors act as a dual-mode breast cancer immunotherapy.

Fluorescent ultrasmall nanoparticles (d < 10 nm), such as carbon nanodots (CDs), are promising nanosystems for precision cancer therapy. Their optimal size allows them to diffuse within complex microenvironments, enabling drug delivery, imaging, and monitoring. Additionally, CDs can be engineered to hold inherent nanotoxicity toward cancer cells, overcoming multidrug resistance associated with conventional drugs. Nevertheless, cancer is a multifactorial disease where combinational strategies are most likely to tackle metastatic tumors and efficiently avoid recidivism. Therefore, developing multifunctional CDs that exhibit intrinsic nanotoxicity against cancer cells and drive effective antitumor immune responses is a promising approach to improving patients' response rates. Here, we developed an innovative nanosystem by conjugating N-,S-doped CDs with indoximod (IND) through a simple and cost-effective method. Our CDs-IND not only retained the advantages of bare CDs, including photoluminescence for self-tracking but also significantly controlled breast cancer progression in vivo following CDs-IND intratumoral (IT) and intravenous (IV) administration. Tumor microenvironment (TME) immune profiling revealed that CDs-IND reduced IDO expression and recruited NK, NKT, and T cells. This study underscores the potential of combining the inherent pharmacological properties of CDs with indoximod-mediated immunotherapy, offering a promising strategy for precision breast cancer treatment.