Nickel(II) Phototheranostics: A Case Study in Photoactivated H2O2-Enhanced Immunotherapy.

Phototheranostics have emerged as a promising subset of cancer theranostics owing to their potential to provide precise photoinduced diagnoses and therapeutic outcomes. However, the design of phototheranostics remains challenging due to the nature of tumors and their microenvironment, including limitations to the oxygen supply, high rates of recurrence and metastasis, and the immunosuppressive state of cancer cells. Here we report a dual-functional oxygen-independent phototheranostic agent, Ni-2, rationally designed to provide a near-infrared (NIR) photoactivated thermal- and hydroxyl radical (•OH)-enhanced photoimmunotherapeutic anticancer response. Under 880 nm laser irradiation, Ni-2 exhibited high photostability and excellent photoacoustic and photothermal effects with a photothermal conversion efficacy of 58.0%, as well as novel photoredox features that allowed the catalytic conversion of H2O2 to •OH upon photooxidation of Ni(II) to Ni(III). As a multifunctional photoagent, Ni-2 was found not only to inhibit tumor growth in a CT26 tumor-bearing mouse model but also to activate an immune response via a combination of photothermal- and H2O2-induced effects. When combined with an antiprogrammed death-ligand 1 (aPD-L1), Ni-2 treatment allowed for the suppression of distant tumor growth and cancer metastasis. Collectively, the present results provide support for the proposition that Ni-2 or its analogues could emerge as useful tools for photoimmunotherapy. They also highlight the potential of appropriately designed 3d transition metal complexes as "all- in-one" phototheranostics.

Ultrasound May Suppress Tumor Growth, Inhibit Inflammation, and Establish Tolerogenesis by Remodeling Innatome via Pathways of ROS, Immune Checkpoints, Cytokines, and Trained Immunity/Tolerance.

BACKGROUND: The immune mechanisms underlying low-intensity ultrasound- (LIUS-) mediated suppression of inflammation and tumorigenesis remain poorly determined. METHODS: We used microarray datasets from the NCBI GEO DataSet repository and conducted comprehensive data-mining analyses, where we examined the gene expression of 1376 innate immune regulators (innatome genes (IGs) in cells treated with LIUS. RESULTS: We made the following findings: (1) LIUS upregulates proinflammatory IGs and downregulates metastasis genes in cancer cells, and LIUS upregulates adaptive immunity pathways but inhibits danger-sensing and inflammation pathways and promote tolerogenic differentiation in bone marrow (BM) cells. (2) LIUS upregulates IGs encoded for proteins localized in the cytoplasm, extracellular space, and others, but downregulates IG proteins localized in nuclear and plasma membranes, and LIUS downregulates phosphatases. (3) LIUS-modulated IGs act partially via several important pathways of reactive oxygen species (ROS), reverse signaling of immune checkpoint receptors B7-H4 and BTNL2, inflammatory cytokines, and static or oscillatory shear stress and heat generation, among which ROS is a dominant mechanism. (4) LIUS upregulates trained immunity enzymes in lymphoma cells and downregulates trained immunity enzymes and presumably establishes trained tolerance in BM cells. (5) LIUS modulates chromatin long-range interactions to differentially regulate IGs expression in cancer cells and noncancer cells. CONCLUSIONS: Our analysis suggests novel molecular mechanisms that are utilized by LIUS to induce tumor suppression and inflammation inhibition. Our findings may lead to development of new treatment protocols for cancers and chronic inflammation.

Eradication of solid tumors by chemodynamic theranostics with H2O2-catalyzed hydroxyl radical burst.

Activatable theranostics, integrating high diagnostic accuracy and significant therapeutic effect, holds great potential for personalized cancer treatments; however, their chemodynamic modality is rarely exploited. Herein, we report a new in situ activatable chemodynamic theranostics PAsc/Fe@Cy7QB to specifically recognize and eradicate cancer cells with H2O2-catalyzed hydroxyl radical (•OH) burst cascade. Methods: The nanomicelles PAsc/Fe@Cy7QB were constructed by self-assembly of acid-responsive copolymers incorporating ascorbates and acid-sensitive Schiff base-Fe2+ complexes as well as H2O2-responsive adjuvant Cy7QB. Results: Upon systematic delivery of PAsc/Fe@Cy7QB into cancer cells, the acidic microenvironment triggered disassembly of the nanomicelles. The released Fe2+ catalyzed the oxidation of ascorbate monoanion (AscH-) to efficiently produce H2O2. The released H2O2, together with the endogenous H2O2, could be converted into highly active •OH via the Fenton reaction, resulting in enhanced Fe-mediated T1 magnetic resonance imaging (MRI). The synchronously released Cy7QB was activated by H2O2 to produce a glutathione (GSH)-scavenger quinone methide to boost the •OH yield and recover the Cy7 dye for fluorescence and photoacoustic imaging. Conclusion: The biodegradable PAsc/Fe@Cy7QB designed for tumor-selective multimodal imaging and high therapeutic effect provides an exemplary paradigm for precise chemodynamic theranostic.