Nano‐Mediated PDT as a Multifunctional Immunomodulatory Agent in the Intricate Milieu of Melanoma

Abstract

The complexity of the tumor microenvironment (TME) and nutrient competition represent the main causes of therapy resistance in cancers, including malignant melanoma (MM). Photodynamic therapy (PDT), through a cascade of events including its ability to induce significant immune responses, causes tumor eradication. However, the high pigmentation level of melanoma, lack of adequate accumulation of photosensitizers (PSs) in the target tissue as well as their nonspecific toxicity represent three main obstacles to obtaining satisfactory responses in melanoma. To prevail over these challenges, this study employed a depigmentation strategy followed by a nano‐mediated topical application of PDT using a chlorophyllin derivative as PS, focusing on evaluation of the immunomodulatory and metabolic regulatory axes of PDT in melanoma. Photo‐immunomodulation was assessed in a melanoma mouse model using a nanocarrier system of the PS. Markers of the immunosuppressive microenvironment and T cell exhaustion, as independent immune hallmarks, were quantified. The histopathology of spleen and skin/tumor was evaluated. The amino acid profile was quantified from normal skin or tumor biopsies using UHPLC‐MS/MS. Around 80% of the 300 nm transethosomal ferrous chlorophyllin (fC‐TEs) were retained in the tumor over 24 h upon topical application. Arbutin 2% gel not only decreased the melanin content of tumors, but also regulated the expression of interleukin 12 (IL‐12), IL‐10, transforming growth factor beta (TGF‐β) and tumor necrosis factor alpha (TNF‐α). Additionally, the nano‐mediated PDT strategy decreased the expression of programmed cell death protein 1 (PD‐1) & its ligand 1 (PD‐L1) and reduced the activity of arginase 1 (Arg1) through an upregulation of miRNA155. A mild recruitment of megakaryocytes (MKs) was observed in the spleen of the PDT group. This special localization of MKs depicts effector immune properties. Lastly, the combination of PDT and arbutin restored the normal tissue levels of arginine (Arg), glutamine (Gln) and lavished those of tryptophan (Trp). Nano‐mediated PDT represents a novel immunotherapeutic approach in melanoma by a triple modulation of the immune suppressive TME, immune checkpoint signaling, and reprogrammed tumor metabolism.This article is protected by copyright. All rights reserved