Manganese ions (Mn²⁺)-coordinated nanoparticles have emerged as a promising class of antitumor nanotherapeutics, capable of simultaneously disrupting the immunosuppressive tumor microenvironment (TME) and triggering the stimulator of interferon genes (STING) pathway-dependent antitumor immunity. However, the activation of STING signaling by Mn²⁺-based monotherapies is suboptimal for comprehensive stimulation of antigen presenting cells and reversal of immunosuppression in the TME. Here, we report the design of a Mn²⁺/CpG oligodeoxynucleotides (ODNs) codecorated black phosphorus nanosheet (BPNS@Mn²⁺/CpG) platform based on the Mn²⁺ modification of BPNS and subsequent adsorption of synthetic CpG ODNs. The coordination of Mn²⁺ significantly improved the stability of BPNS and the adsorption of CpG ODNs. The acidic TME and endosomal compartments can disrupt the Mn²⁺ coordination, triggering pH-responsive release of CpG ODNs and Mn²⁺ to effectively activate the Toll-like receptor 9 and STING pathways. As a result, M2-type macrophages and immature dendritic cells were strongly stimulated in the TME, thereby increasing T lymphocyte infiltration and reversing the immunosuppression within the TME. Phototherapy and chemodynamic therapy, utilizing the BPNS@Mn²⁺/CpG platform, have demonstrated efficacy in inducing immunogenic cell death upon 808 nm laser irradiation. Importantly, the treatment of BPNS@Mn²⁺/CpG with laser irradiation exhibited significant therapeutic efficacy against the irradiated primary tumor and effectively suppressed the growth of nonirradiated distant tumor. Moreover, it induced a robust immune memory, providing long-lasting protection against tumor recurrence. This study demonstrated the enhanced antitumor potency of BPNS@Mn²⁺/CpG in multimodal therapy, and its proof-of-concept application as a metal ion-modified BPNS material for effective DNA/drug delivery and immunotherapy.

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