TY - EJOU
AU - Zheng, Yu
AU - Zheng, Peng
AU - Zheng, Yidan
AU - Xi, Zihan
AU - Huang, Tao
TI - Liposomal Doxorubicin Induces PD-L1-High Tumor-Associated Macrophages and Sensitizes Triple-Negative Breast Cancer to PD-L1 Blockade
T2 - Oncology Research
PY - 2026
VL - 34
IS - 10
SN - 1555-3906
AB - Objective: Liposomal doxorubicin (L-DOX) may alter macrophage-mediated immune regulation in triple-negative breast cancer (TNBC), but its role in programmed death-ligand 1 (PD-L1)-associated immune escape remains unclear. This study aimed to determine whether L-DOX induces a macrophage-centered PD-L1 response and affects the efficacy of PD-L1 blockade in TNBC. Methods: Public bulk and single-cell transcriptomic datasets, bone marrow-derived macrophage models, CD8+ T-cell co-culture assays, promoter-binding analyses, and syngeneic EO771 and 4T1 TNBC mouse models were used to examine PD-L1 regulation and immune function after L-DOX treatment. Results: The principal findings were that L-DOX preferentially induced a PD-L1-high macrophage state and sensitized TNBC tumors to PD-L1 blockade. DOX-containing therapy was associated with PD-L1 upregulation enriched in tumor-associated macrophages, and L-DOX induced stronger macrophage PD-L1 expression than free DOX or taxane-based agents. Mechanistically, L-DOX accumulation triggered DNA damage-associated ATM-p53 and cGAS-STING signaling, leading to RELA/p65-dependent NF-κB activation and PD-L1 transcription. Functionally, L-DOX-conditioned macrophages suppressed CD8+ T-cell activation, proliferation, and tumor-cell killing, whereas PD-L1 blockade restored CD8+ effector function, promoted pro-inflammatory macrophage features, and improved tumor control in EO771 and 4T1 models compared with either monotherapy. Conclusion: L-DOX induces a PD-L1-high macrophage state with immunosuppressive features that constrains antitumor T-cell responses. Combining L-DOX with PD-L1 blockade may provide a rational chemoimmunotherapy strategy for TNBC.
KW - Liposomal doxorubicin; tumor-associated macrophages; programmed death-ligand 1 (PD-L1); triple-negative breast cancer; neoadjuvant chemotherapy
DO - 10.32604/or.2026.087138