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Immunogenic photodynamic therapy (PDT) has the potential to moderate the shortfalls of cancer immunotherapy. However, its efficacy is severely limited particularly because of the lack of optimal photosensitizers and smart delivery processes and the inherent shortcomings of PDT (e.g., hypoxia resistance). Here, we demonstrate a clinically promising approach that utilizes a water-soluble phthalocyanine derivative (PcN4) concomitantly delivered with a hypoxia-activated prodrug (AQ4N) to amplify the effect of PDT and enhance cancer immunotherapy. After intravenous injection, PcN4 selectively interacted with endogenous albumin dimers and formed supramolecular complexes, providing a facile and green approach for tumor-targeted PDT. The concomitant delivery of AQ4N overcame the limitations of hypoxia in PDT and improved the antitumor activity of PDT. Treatment with PcN4-mediated and AQ4N-amplified PDT almost completely eradicated sizable primary tumors in a triple-negative breast cancer model and significantly activated CD8 + T cells. As the majority of tumor infiltrating CD8 + T cells were both PD-1- and TIM3-positive, additional combination therapy using PD-L1/PD-1 pathway blockade was warranted. After combination with immune checkpoint blockade treatment, an enhanced abscopal effect was achieved in both distant and metastatic tumors., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

BMP-9, whose expression is highest in liver cells, has been demonstrated to regulate expression of enzymes involved in glucose homeostasis. However, the underlying mechanism of this effect has yet to be elucidated. We observed that MB109, a recombinant BMP-9 derivative, enhanced brown adipogenesis of human adipose tissue derived stem cells. With this observation of the cell culture system, we hypothesized that MB109 may be able to improve glucose metabolism by regulating expression of brown adipogenic genes. Systemic intraperitoneal injection of MB109 (200 μg/kg/wk) suppressed weight gaining of high fat diet-induced obese mice by reducing sizes of white adipocytes and decreased 16 h fasting blood glucose levels without changing food consumption or apparent behavioral performances. MB109 induced expression of brown adipogenic genes in the subcutaneous but not in the visceral fat tissues from the mice fed with high fat diet. In addition, systematic injection of MB109 enhanced fatty acid synthase expression in the liver of obese mice, which may help attenuate an obesity-associated increase of blood glucose levels. Our results demonstrate a role of BMP-9 in brown adipogenesis and suppressing pathophysiology of high fat diet-induced obesity, presumably through the activin receptor like kinase 1 signaling pathway., (Copyright © 2013 Elsevier Ltd. All rights reserved.)