Arsenene-Vanadene nanodots co-activate Apoptosis/Ferroptosis for enhanced chemo-immunotherapy

Abstract

Triple-Negative Breast Cancer (TNBC) represents a highly aggressive subtype of breast cancer with an unfavorable prognosis, characterized by minimal immune infiltration and pronounced immune suppression, resulting in a limited response to immunotherapy. In this study, a multifunctional Arsenene-Vanadene nanodot (AsV) drug delivery system is introduced, which responds to the tumor microenvironment by releasing arsenic and vanadium. Arsenic undergoes oxidation to generate highly toxic trivalent arsenic, which induces apoptosis in tumor cells while utilizing apoptotic cell debris to transiently activate the immune system. Additionally, arsenic binds to cysteine, indirectly facilitating ferroptosis. Concurrently, vanadium's redox cycling properties are harnessed to trigger a Fenton-like reaction, promoting lipid peroxidation. Furthermore, ferroptosis is enhanced through the depletion of glutathione and inactivation of glutathione peroxidase 4 (GPX4), leading to the release of damage-associated molecular patterns and thereby amplifying the anti-tumor immune response. This study represents the first instance of integrating arsenene's apoptosis-inducing properties with vanadium's ferroptosis-enhancing effects, providing a synergistic approach to improving the immunotherapeutic response and offering a potential strategy for enhancing TNBC prognosis.

Statement of Significance

Triple-negative breast cancer (TNBC) exhibits resistance to immunotherapy due to its highly immunosuppressive tumor microenvironment. In this study, tumour-responsive Arsenene-Vanadene nanodots (AsV) were developed to induce a synergistic effect by triggering apoptosis and ferroptosis through microenvironment-specific mechanisms. The arsenic component generates cytotoxic trivalent arsenic, promoting apoptosis while binding to cysteine, thereby reducing GSH synthesis. Simultaneously, vanadium initiates lipid peroxidation through Fenton-like reactions and disruption of the glutathione/GPX4 axis, further amplifying ferroptotic cell death. This dual-action system transforms tumor cell debris into immune-stimulating signals while circumventing conventional immunotherapy limitations. As the first strategy integrating arsenic-induced apoptosis with vanadium-enhanced ferroptosis, this approach provides a mechanistic framework to overcome TNBC immunosuppression through coordinated cell death pathways, demonstrating potential for precision nanomedicine applications.