Enhancing immunotherapy using a synergistic T-lymphocyte and neutrophil-targeting activation (TNTa) strategy for triple-negative breast cancer treatment

Immunotherapy has shown enormous potential for cancer treatment, but the number of patients who have benefited remains limited owing to the immunologically cold nature of tumors. The induction of immunogenic cell death (ICD) and activation of the cGAS-STING pathway can reprogram the immune microenvironment, enhancing T-cell-dependent antitumor immune responses. However, tumors can lead to the development of low-immunogenicity and antigen-negative characteristics to evade recognition and survive T-lymphocyte-mediated antitumor immunotherapy. Neutrophils are the most abundant circulating leukocytes in the body, which have the potential to enhance immunotherapy by eliminating antigen loss variants via a tumor antigen-independent pathway. In this study, a novel method of enhancing immunotherapy using a synergistic T-lymphocyte and neutrophil-targeting activation (TNTa) strategy was developed by using DOX&LPS@MnO_x-PEG (DLMP) nanoplatforms. Tumor microenvironment (TME)-responsive DLMP releases DOX and Mn²⁺ for tumor-specific chemo/chemodynamic therapy, leading to ICD and cGAS-STING pathway activation, reshaping the immune microenvironment, and facilitating T-cell-mediated immune responses. However, co-delivery of the immune adjuvant lipopolysaccharide (LPS) leads to neutrophil recruitment at the tumor site, eliminating tumor antigen loss variants. In vivo experiments demonstrated that enhanced immunotherapy could be achieved using this DLMP mediated TNTa strategy, providing a new approach to tumor immunotherapy.