Reversing adenosine-mediated immunosuppression in triple-negative breast cancer by synergistic chemo-immunotherapy via stimuli-responsive nanomedicines.

BACKGROUND: Chemotherapy remains the first-line treatment for triple-negative breast cancer (TNBC). Anthracycline chemotherapeutics, such as epirubicin (EPI), not only kill tumor cells but also induce immunogenic cell death (ICD). However, accumulated extracellular adenosine triphosphate (eATP) during ICD is converted to adenosine, triggering immunosuppression via adenosine receptor signalling. To address this issue, co-administration of EPI with adenosine receptor antagonists could remodel the immunosuppressive tumor microenvironment and potentiate antitumor immunity. METHODS: The effect of the expression level of adenosine receptors on the immune microenvironment of TNBC was assessed by integrating bioinformatic analysis of public databases with immunofluorescence staining of TNBC clinical samples. Four polymeric prodrugs of EPI were synthesised, and their delivery performances were assessed. A nanomedicine with pH/cathepsin B (CTSB)-responsiveness for co-delivery of EPI and AB928 (an adenosine receptor antagonist) was constructed. The cellular experiments and 4T1 tumor-bearing mice model were employed to evaluate antitumor efficacy. FINDINGS: Bioinformatic analyses and immunofluorescence staining of TNBC clinical samples supported the rationale for combining ICD-inducing chemotherapeutic agents with adenosine receptor antagonists. The polymeric prodrug of EPI with an optimal delivery efficiency was selected to encapsulate AB928. The constructed nanomedicine for EPI/AB928 co-delivery enhanced antitumor immune responses by effectively inhibiting adenosine-A2A receptor/A2B receptor (A2AR/A2BR) signalling pathways and reversing adenosine-mediated immunosuppression. INTERPRETATION: Co-delivery of an ICD inducer (EPI) and an adenosine receptor antagonist (AB928) is realised in a stimuli-responsive nanomedicine to address immunosuppression induced by adenosine, thereby enhancing ICD effects and synergistically reprogramming the immunosuppressive tumor microenvironment. FUNDING: See Acknowledgements.