Robust Photodynamic Therapy Using 5‐ALA‐Incorporated Nanocomplexes Cures Metastatic Melanoma through Priming of CD4⁺CD8⁺ Double Positive T Cells

Abstract

Advanced melanoma can rarely be cured. Photodynamic therapy (PDT) readily eradicates the primary melanoma but has limited ability to destroy the spreading tumor cells unless supported by other combinative interventions to augment systemic antitumor immunity. Based on the previously synthesized penetration‐enhancing biomaterials, a topically administered nanoformulation is developed, which profoundly assists 5‐aminolevulinic acid (5‐ALA) in circumventing skin barrier to be selectively delivered to tumor cells. After endocytosis, accumulated 5‐ALA is efficiently metabolized to a photosensitizer protoporphyrin IX (PpIX) which stimulates a large production of cytotoxic reactive oxygen species (ROS) under illumination. Accompanied by the robust inflammatory responses followed by primary tumor destruction, CD4+CD8+ double positive T cells are highly boosted to harness host immunity to purge metastases in lymphoid organs. Compared with dacarbazine and programmed death 1 (PD‐1) antibody, this treatment in advanced melanoma murine models, achieves a striking curable rate of 90% without melanoma prognostic markers LDH and S‐100B detection, followed by a relapse‐free survival rate of 83.33% in 300 days. Moreover, the cured mice's immune system function recovers to an extent similar to healthy mice without prolonged or exaggerated inflammation. This study using the synergistic biomaterials approach may thus render 5‐ALA‐mediated PDT a potentially curative therapy for advanced melanoma in clinic.

Dissolving Microneedles with Spatiotemporally controlled pulsatile release Nanosystem for Synergistic Chemo-photothermal Therapy of Melanoma

“…Skin cancers represent a growing proportion of all human cancers and are associated with high mortality 1 . Although it only accounts for 4% of all skin cancer cases, malignant melanoma is the main cause of death in superficial skin tumors 2 , 3 . Surgery and chemotherapy are the major treatments for malignant melanoma.…”

Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species

“…ROS are also related to immunogens and tolerogenic processes[ 24 ]. The increased systemic immunity or enhanced tumor immunity induced by PDT may also be mediated by ROS[ 25 ]. Currently, although little is known about whether or how ROS are involved in stem cell immunity, it has been determined that identifying the mechanism by which ROS metabolism affects the fate of stem cells will promote the necessary understanding to apply PDT to inhibit the spread of distant cancer stem cells.…”

“…Although PDT is used to treat superficial malignancies, its immunogenicity has the potential to eliminate systemic CSCs. But in a counterintuitive outcome, some research found that low-dose PDT promotes tumor cells metastasis[ 25 , 26 ]. The epithelial-mesenchymal transition (EMT) has been shown to be one of the causes of cancer cell migration and invasion[ 27 ].…”

Preclinical and Clinical Evidence of Immune Responses Triggered in Oncologic Photodynamic Therapy: Clinical Recommendations

“…In contrast, not much information about the ALA-PDT induced adaptive immunity is available. A study has shown that memory T cells (CD44 hi CD62L hi ) accumulate in the tumor and spleen of ALA-PDT treated mice [60]. and activation.…”