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

Authors

Zhenyu Xu, Shengyi Wang, Yiyang Cao, Jianing Song, Yinghuan Liu, Rong Zhang, Xulin Tang, Ya Wang, Haodi Wu, Jiasheng Tu, Qian Chen, Chunmeng Sun

Published in

Acta pharmaceutica Sinica. B. Volume 16. Issue 9. Pages 6235-6252. Epub Jul 17, 2026.

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.

PMID:
42765032
Bibliographic data and abstract were imported from PubMed on 21 Sep 2026.

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