Oxygen-vacancy MoO3-x nanodots induce immunogenic cell death and STING activation for synergistic cancer immunotherapy.

Cancer therapy has been revolutionized by immune checkpoint inhibitor (ICI) therapies, yet the "cold" tumor microenvironment (TME) often resists immunotherapy. Combining immunogenic cell death (ICD) induction with STING (stimulator of interferon genes) pathway activation represents a promising strategy to promote dendritic cell (DC) maturation and T-cell immunity. However, challenges such as inefficient ICD induction in solid tumors, the use of toxic metal cations, or the instability of STING agonists limit therapeutic durability. Here, we developed liposome-encapsulated oxygen-vacancy-engineered MoO3-x nanodots (MoO3-x@Lip NPs) as a multifunctional nanoplatform for enhanced cancer immunotherapy via photothermal therapy (PTT), chemodynamic therapy (CDT), and STING activation. In the TME, MoO3-x@Lip NPs accumulate effectively, generating photothermal effects and catalytically producing cytotoxic hydroxyl radicals via hydrogen peroxide decomposition, which potently induces ICD. Concurrently, released MoO₄2- activates the cGAS-STING pathway, promoting DC maturation and type I interferon secretion. This dual mechanism significantly enhances intratumoral CD8+ T-cell infiltration, reduces immunosuppressive Treg cell populations, and modulates pro-inflammatory cytokine profiles, leading to robust primary tumor regression. Notably, the immunogenic TME reshaped by MoO3-x@Lip NPs synergizes with anti-PD-1 checkpoint blockade, eliciting systemic antitumor responses that suppress both primary and distal tumors in a bilateral model. RNA sequencing revealed upregulation of immune-related pathways (e.g., cytokine-receptor interaction, PD-L1/PD-1 signaling) and downregulation of oncogenic processes. Collectively, this nanosystem integrates PTT/CDT with STING-driven immune activation, offering a safe and effective strategy to convert "cold" tumors into immunologically "hot" phenotypes for synergistic cancer therapy.