Biomimetic nanovesicle with tri-pronged immune amplification for efficient photo-immunotherapy against triple-negative breast cancer.

The limited response to immune checkpoint blockade (ICB) in triple-negative breast cancer (TNBC) is driven by both low intrinsic immunogenicity and a profoundly immunosuppressive tumor microenvironment (TME). Stimulator of interferon genes (STING) activation is a significant strategy to remodel the immunosuppressive TME by improving dendritic cells (DCs) maturation and M1-like macrophage polarization. However, the clinical translation of STING agonists is hampered by insufficient delivery efficiency. Herein, we integrate the 2',3'-cGAMP, a kind of cyclic dinucleotide (CDN), with indocyanine green (ICG) into PD-1 overexpressed cell membrane vesicles (named as CDN@PM-ICG) for photo-immunotherapy. After systemic administration, CDN@PM-ICG nanovesicles accumulated at tumor region through high-affinity binding to PD-L1 overexpressed on neoplastic cells, effectively inhibiting the PD-1/PD-L1 axis and potentiating localized STING agonist delivery. Upon laser irradiation, ICG-mediated phototherapy induces immunogenic cell death (ICD), thereby elevating tumor immunogenicity and liberating damage associated molecular patterns (DAMPs). Subsequently, the released DAMPs, in combination with the STING activation, synergistically induces the maturation of DCs and promote the repolarization of tumor-associated macrophages (TAMs) toward the M1-like phenotype. This tri-pronged ICB/ICD/STING modulation paradigm augments cytotoxic T lymphocytes (CTLs) infiltration and ultimately inhibits tumor progression in a TNBC mouse model.