Li Liu

Background: Melanoma represents a highly aggressive and immunotherapy-resistant malignancy with limited immunotherapy efficacy, underscoring the urgent need for novel treatment strategies that integrate precise diagnosis and potent immunomodulation. The combination of photothermal therapy (PTT) and STING pathway activation has emerged as a promising approach to potentiate antitumor immunity. Nevertheless, it remains challenging to integrate real-time deep-tissue imaging with spatiotemporally synchronized immunostimulation within a single nanoplatform, especially for the effective treatment of advanced melanoma. Results: Herein, we report a mitochondria-targeted nanotheranostic agent (IRM) constructed through molecular co-assembly of a STING agonist (MSA-2) and a lab-synthesized NIR-Ⅱ fluorophore (IR-817). This nanoplatform enables simultaneous NIR-Ⅱ fluorescence imaging and high-efficiency photothermal conversion (η = 52.79%). More importantly, it ensures efficient, on-demand drug action through spatiotemporally controlled delivery. Under 808 nm laser irradiation, IRM induced localized hyperthermia that provoked pyroptosis and immunogenic cell death (ICD) in primary melanoma tumors. Concurrently, the photothermal stimulus promoted the rapid release of MSA-2, which synergistically activated the STING pathway in dendritic cells (DCs). This event drove immunometabolic reprogramming of the tumor microenvironment, elicited a robust systemic cytotoxic T-cell response, and effectively reversed the immunosuppressive state. This cascade of biological events ultimately led to significant inhibition of distant tumors, demonstrating a robust abscopal effect. Crucially, this therapeutic effect was strictly STING-dependent: in STING -KO mouse models, the suppression of distant tumors was completely abolished following the same treatment. These complementary experimental outcomes directly confirm the indispensable synergy between PTT and STING pathway activation, which together constitute the core mechanism underlying the induction of systemic antitumor immunity by the IRM nanoplatform. Conclusions: Our study illustrates that the IRM nanoplatform effectively merges multimodal imaging with immunometabolic modulation, establishing a durable and systemic antitumor immunity. This work offers a translatable strategy for combinational photo-immunotherapy against advanced melanoma. Graphical

Near‐infrared (NIR) fluorescence imaging, a novel non‐invasive diagnostic tool, plays a pivotal role in the imaging and monitoring of solid tumors. As core fluorescent probes, NIR fluorescent dyes are widely utilized in biological imaging, primarily due to their capacity to mitigate tissue autofluorescence interference—an attribute that notably enhances the signal‐to‐noise ratio (SNR) and detection selectivity. Mitochondria are indispensable for a spectrum of biological processes, and their dysfunction is closely associated with the metastatic potential and drug resistance of tumor cells; this renders mitochondria‐targeted cyanine dyes highly valuable for research. The functionalization of cyanine dyes can be achieved through three key strategies: (1) introducing active groups into the parent core structure; (2) constructing novel dyes tailored for in vivo imaging and histological analyses; (3) exploring combinations with biological materials. These approaches can significantly modulate the intrinsic properties of cyanine dyes, thereby endowing them with diverse fluorescence imaging functionalities. Recent studies have demonstrated that such modified mitochondria‐targeting cyanine dyes have been successfully applied in the detection of pH fluctuations, metal ions, and oxidative damage, as well as in the targeted imaging of tumor cells. This review summarizes the latest research progress of these probes in the field of biological imaging over recent years.

Background: Melanoma is a highly invasive and metastatic skin cancer lacking effective options for early diagnosis and treatment. To address these challenges, this study aimed to synthesize a novel near-infrared fluorescent probe and research the antitumor mechanism of melanoma. Methods: We have designed and synthesized a novel near-infrared fluorescent probe, IR-546. This study explores imaging capabilities, anti-tumor effects, and underlying mechanisms of IR-546 in melanoma xenograft models. Results: In vitro, IR-546 selectively accumulates in melanoma cells, demonstrating robust tumor imaging and potent cytotoxicity by targeting mitochondria, generating reactive oxygen species (ROS), and disrupting mitochondrial membrane potential, activating the mitochondrial apoptotic pathway. Additionally, IR-546 exhibits anti-metastatic properties in vitro. In vivo, using A375 cell line-derived melanoma xenograft models, IR-546 showed significant anti-tumor effect and biosafety. Western blot analyses of both in vivo and in vitro revealed that IR-546 induces apoptosis and inhibits metastasis of melanoma by activating the mitochondrial apoptosis pathway, suppressing the AKT/GSK3β signaling pathway, and downregulating the β-catenin signaling pathway and its downstream targets. Immunohistochemistry and immunofluorescence further confirmed that IR-546 suppressed the expression of key proteins in the AKT/GSK3β pathway in vivo. Conclusions: Collectively, these findings highlight IR-546 as a promising tool for both imaging and treatment of melanoma, with the potential to induce apoptosis and inhibit metastasis of melanoma through modulation of the AKT/GSK3β pathway. Graphical Summary of the diagnostic and anti-tumor effects of IR-546 in melanoma.

Purpose Melanoma is a malignant skin tumor caused by melanocytes and associated with high mortality rates. This study aims to investigate the specific mechanism of ZWZ-3 in melanoma proliferation and metastasis. Methods RNA sequencing was performed to identify the effect of ZWZ-3 on gene expression. siRNA was used to inhibit BIRC5 gene expression in the B16F10 cell line. A zebrafish tumor model was used to assess the therapeutic effect of ZWZ-3 in vivo. Mechanistic insights into the inhibition of tumor metastasis by ZWZ-3 were obtained through analysis of tumor tissue sections in mice. Results Our findings demonstrated that ZWZ-3 suppressed melanoma cell proliferation and migration. We performed RNA sequencing in melanoma cells after the treatment with ZWZ-3 and found that Birc5, which is closely associated with tumor metastasis, was significantly down-regulated. Bioinformatics analysis and the immuno-histochemical results of tissue chips for melanoma further confirmed the high expression of BIRC5 in melanoma and its effect on disease progression. Moreover, Birc5 knock-down significantly inhibited melanoma cell proliferation and metastasis, which was correlated with the β-catenin/HIF-1α/VEGF/MMPs pathway. Additionally, ZWZ-3 significantly inhibited tumor growth in the zebrafish tumor model without any evident side effects. Histological and immuno-histochemical analyses revealed that ZWZ-3 inhibited tumor cell metastasis by down-regulating HIF-1α, VEGF, and MMP9. Conclusion Our findings revealed that ZWZ-3 could downregulate BIRC5 and inhibit melanoma proliferation and metastasis through the β-catenin/HIF-1α/VEGF/MMPs pathway. Therefore, BIRC5 represents a promising therapeutic target for the treatment of melanoma.

Background: Near-infrared cyanine dyes have high sensitivity and spatial resolution imaging capabilities, but they also have unavoidable drawbacks such as photobleaching, low water solubility, fluorescence quenching, and toxic side effects. As an effective biologic drug carrier, albumin combines with cyanine dyes to form albumin@dye nanoparticles. These nanoparticles can alleviate the aforementioned issues and are widely used in tumor imaging and photothermal therapy. Methods: Herein, a newly synthesized near-infrared dye IR-817 was combined with bovine serum albumin (BSA) to create BSA@IR-817 nanoparticles. Through the detection of fluorescence emission and absorption, the optimal concentration and ratio of BSA and IR-817 were determined. Subsequently, dynamic light scattering (DLS) measurements and scanning electron microscopy (SEM) were used for the physical characterization of the BSA@IR-817 nanoparticles. Finally, in vitro and in vivo experiments were conducted to assess the fluorescence imaging and photothermal therapeutic potential of BSA@IR-817 nanoparticles. Results: IR-817 was adsorbed onto the BSA carrier by covalent conjugation and supramolecular encapsulation, resulting in the formation of dispersed, homogeneous, and stable nanoparticles with a particle size range of 120-220 nm. BSA@IR-817 not only improved the poor water solubility, fluorescence quenching, and toxic side effects of IR-817 but also enhanced the absorption and fluorescence emission peaks in the near-infrared region, as well as the fluorescence in the visible spectrum. In addition, BSA@IR-817 combined with laser 808 irradiation was able to convert light energy into heat energy with temperatures exceeding 50 degrees C. By creating a mouse model of subcutaneous melanoma, it was discovered that the tumor inhibition rate of BSA@IR-817 was greater than 99% after laser irradiation and that it achieved nearly complete tumor ablation without causing significant toxicity. Conclusion: Our research, therefore, proposes the use of safe and effective photothermal nanoparticles for the imaging, diagnosis, and treatment of melanoma, and offers a promising strategy for future biomedical applications.