GSH‐Responsive Mn2+ Burst Nanoboxes as Mitophagy Intervention Agents Augment Ferroptosis and Chemoimmunotherapy in Triple‐Negative Breast Cancer

Abstract Chemoimmunotherapy is recognized as a promising approach for treating cancer patients. However, the overall therapeutic efficacy of treatments for triple‐negative breast cancer (TNBC) is compromised by several factors, including its highly immunosuppressive tumor microenvironment, the presence of drug‐resistant cells, and the upregulation of PD‐L1 expression induced by chemotherapy. In this study, a GSH‐responsive, transferrin‐targeted hollow manganese drug‐loaded nanobox, employing a strategy to regulate tumor redox balance for integrated MR imaging and treatment, is developed. These nanoboxes enhance chemotherapy sensitivity by activating mitophagy to sensitize ferroptosis and thereby inducing the release of damage‐associated molecular patterns (DAMPs) and mitochondrial DNA (mtDNA) from cancer cells. The GSH‐responsive release of Mn 2 ⁺, in combination with free DNA, collectively mediates the activation of the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway, thereby ameliorating the immunosuppressive microenvironment. Simultaneously, mtROS‐mediated activation of AMP‐activated protein kinase (AMPK) overcomes chemotherapy‐induced PD‐L1 treatment resistance by inducing PD‐L1 degradation in tumor cells. Additionally, this process allows for in vitro MR detection of GSH responsiveness and efficient drug delivery. This innovative approach leveraging the interplay of mitophagy and ferroptosis to overcome chemotherapy resistance and immune suppression and enables treatment monitoring.