Combination of YAP inhibition and photodynamic therapy induces dual DNA damage and activates STING pathway to enhance immunotherapy in uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and is highly aggressive, with no therapies shown to improve overall survival. Although immunotherapy achieves response rates of 33-40 % in advanced cutaneous melanoma, its efficacy in UM is disappointingly low, with only 3.6 % of patients responding. Herein, we report a nanomedicine-based strategy to enhance immunotherapy efficacy in UM by strong activation of the cyclic guanosine 3',5'-cyclic monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway through dual deoxyribonucleic acid (DNA) damage induced by Yes-associated protein (YAP) inhibition and photodynamic therapy (PDT). This approach, using hyaluronic acid nanoparticle (HANP)-formulated verteporfin (HANP/VP), concurrently induced nuclear- and mitochondrial-DNA damage, promoted immunogenic cell death (ICD), and drove T-lymphocyte infiltration into the tumor microenvironment (TME). When combined with anti-programmed death-ligand 1 (anti-PD-L1) antibody (Ab) and laser radiation (690 nm, 200 mW/cm2, 10 min), HANP/VP significantly increased production of the pro-inflammatory cytokines interferon-γ (IFN-γ), IFN-β1, and tumor necrosis factor-α (TNF-α), enhanced dendritic-cell (DC) maturation and Cluster of Differentiation 8-positive (CD8+) T-cell expansion, suppressed tumor growth by 96.20 ± 7.22 %, and extended survival from 33 to >80 days in orthotopic UM models. Importantly, rechallenge experiments confirmed durable antitumor immunity and prevention of UM recurrence. Overall, our findings established HANP/VP as a multifunctional nanomedicine that reprogrammed the TME and elicited potent antitumor immunity through dual DNA damage and STING activation. The study highlights a promising translational strategy for overcoming immunotherapeutic resistance in UM and converting immunologically "cold" tumors into "hot" ones, thereby improving responses to immune checkpoint blockade (ICB).