Photothermal-driven sequential immunotherapy overcomes resistance to PARP inhibition in Brca1-deficient triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) faces formidable clinical challenges due to target scarcity and a profound immunosuppressive microenvironment, necessitating innovative therapeutic strategies. Although poly ADP-ribose polymerase inhibitors leverage synthetic lethality in BRCA-mutated tumors, their efficacy is subverted by tumor-associated macrophages (TAMs)-driven immunosuppression, and current combinatorial strategies fail to overcome these resistance barriers. To address this, we engineered a thermo-responsive double-layer gel for spatiotemporally coordinated delivery: mild photothermal therapy reprograms TAMs to dismantle immunosuppressive niches, poly ADP-ribose polymerase inhibitors induce immunogenic tumor death releasing damage-associated molecular patterns, and delayed anti-CD47 antibodies release blocks the CD47-signal regulatory protein α axis. In Brca1-deficient TNBC models, this strategy demonstrated: (1) mild photothermal therapy-activated stimulator of interferon genes pathway triggering TAMs repolarization, (2) tumor-derived double-stranded DNA reinforcing the anti-tumor phenotypes, and (3) anti-CD47 antibody-enhanced phagocytosis and T cell activation via antigen cross-presentation. Consequently, this strategy controlled orthotopic/distal tumors and lung metastases by remodeling the immunosuppressive microenvironment. Our work not only unveils a novel mechanism of physical energy-mediated immune modulation but also establishes a paradigm shift for TNBC therapy, from empirical drug combinations to rationally designed spatiotemporal cascades.