Gancotamab(Merrimack Pharmaceuticals, Inc.)

A multi-functional single-Fe-atom nanozyme (Fe-SAzyme) is designed, integrating the near-infrared photothermal property, the ability to carry chemoagent (doxorubicin - DOX), and nanocatalytic activities mimicking peroxidase, oxidase, and glutathione oxidase. The nanocatalytic activities act cooperatively to effectively produce cytotoxic radicals in the tumor microenvironment (TME), thereby leading to ferroptosis of cancer cells. The photothermal effect not only enhances the nanocatalytic therapy but also enables photothermal therapy. And release of DOX upon triggering by TME and the Fe-SAzyme activities enables chemotherapy to induce apoptosis of cancer cells. Such targeted and synergistic multi-modality treatment achieves complete tumor elimination without obvious side effects. Further, the underlying working mechanism is carefully revealed both theoretically and experimentally.

Immunotherapy has transformed cancer treatment, but its efficacy is often limited by the immunosuppressive characteristics of the tumor microenvironment (TME), which are predominantly influenced by the metabolism of cancer cells. Among these metabolic pathways, the indoleamine 2,3-dioxygenase (IDO) pathway is particularly crucial, as it significantly contributes to TME suppression and influences immune cell activity. Additionally, inducing immunogenic cell death (ICD) in tumor cells can reverse the immunosuppressive TME, thereby enhancing the efficacy of immunotherapy. Herein, we develop CGDMRR, a novel bimetallic peroxide-based nanodrug based on copper-cerium peroxide nanoparticles. These nanotherapeutics are engineered to mitigate tumor hypoxia and deliver therapeutics such as 1-methyltryptophan (1MT), glucose oxidase (GOx), and doxorubicin (Dox) in a targeted manner. The design aims to alleviate tumor hypoxia, reduce the immunosuppressive effects of the IDO pathway, and promote ICD. CGDMRR effectively inhibits the growth of 4T1 tumors and elicits antitumor immune responses by leveraging immunometabolic interventions and therapies that induce ICD. Furthermore, when CGDMRR is combined with a clinically certified anti-PD-L1 antibody, its efficacy in inhibiting tumor growth is enhanced. This improved efficacy extends beyond unilateral tumor models, also affecting bilateral tumors and lung metastases, due to the activation of systemic antitumor immunity. This study underscores CGDMRR's potential to augment the efficacy of PD-L1 blockade in breast cancer immunotherapy.