A Triple-Kill Strategy for Tumor Eradication Reinforced by Metal-Phenolic Network Nanopumps

Stress response to radiation sensitizes immunologically nonresponsive tumors to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy. The combination of radiotherapy (RT) and CTLA-4 immune checkpoint blockade therapy has been clinically adopted and has yielded outstanding cooperative effects from restricted local lethality to systemic immune response. However, this combination therapy induces resistance caused by T cell depletion and increased programmed death-ligand 1 (PD-L1) expression in tumor cells. Hence, suppressing PD-L1 expression through RT coupled with anti-CTLA-4 therapy can directly and efficiently address tumor resistance. Herein, metal-phenolic network is incorporated into a triple combination therapy. Hafnium, a radiosensitizer used in clinical studies, is coordinated with polyphenols to constitute the principal structure of nanopumps (AHSC NPs). AHSC NPs embedded with atovaquone and sabutoclax could alleviate hypoxia and accelerate the activation of the apoptosis signaling pathway. Clinical/preclinical materials and approaches are employed as foundations and innovatively incorporate AHSC NPs to furnish a research basis and reference value for the integration of nanotechnology into clinical trials.