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Non-melanoma skin cancer has recently seen an increase in prevalence, and it is estimated that this grow will continue in the coming years. In this sense, the importance of therapy effectiveness has increased, especially photodynamic therapy. Photodynamic therapy has attracted much attention as a minimally invasive, selective and repeatable approach for skin cancer treatment and prevention. Although its high efficiency, this strategy has also faced problems related to tumor resistance, where the tumor microenvironment has gained a well-deserved role in recent years. Tumor microenvironment denotes a wide variety of elements, such as cancer-associated fibroblasts, immune cells, endothelial cells or the extracellular matrix, where their interaction and the secretion of a wide diversity of cytokines. Therefore, the need of designing new strategies targeting elements of the tumor microenvironment to overcome the observed resistance has become evident. To this end, in this review we focus on the role of cancer-associated fibroblasts and tumor-associated macrophages in the resistance to photodynamic therapy. We are also exploring new approaches consisting in the combination of new and old drugs targeting these cells with photodynamic therapy to enhance treatment outcomes of non-melanoma skin cancer.

Cancer metabolic reprogramming promotes resistance to therapies. In this study, we addressed the role of the Warburg effect in the resistance to photodynamic therapy (PDT) in skin squamous cell carcinoma (sSCC). Furthermore, we assessed the effect of metformin treatment, an antidiabetic type II drug that modulates metabolism, as adjuvant to PDT. Methods: For that, we have used two human SCC cell lines: SCC13 and A431, called parental (P) and from these cell lines we have generated the corresponding PDT resistant cells (10GT). Results: Here, we show that 10GT cells induced metabolic reprogramming to an enhanced aerobic glycolysis and reduced activity of oxidative phosphorylation, which could influence the response to PDT. This result was also confirmed in P and 10GT SCC13 tumors developed in mice. The treatment with metformin caused a reduction in aerobic glycolysis and an increase in oxidative phosphorylation in 10GT sSCC cells. Finally, the combination of metformin with PDT improved the cytotoxic effects on P and 10GT cells. The combined treatment induced an increase in the protoporphyrin IX production, in the reactive oxygen species generation and in the AMPK expression and produced the inhibition of AKT/mTOR pathway. The greater efficacy of combined treatments was also seen in vivo, in xenografts of P and 10GT SCC13 cells. Conclusions: Altogether, our results reveal that PDT resistance implies, at least partially, a metabolic reprogramming towards aerobic glycolysis that is prevented by metformin treatment. Therefore, metformin may constitute an excellent adjuvant for PDT in sSCC, This research was supported by Spanish grants from Instituto de Salud Carlos III MINECO and Feder Funds (FIS PI15/00974; PI18/00858 and PI18/00708) and Ministerio de Ciencia, Innovación y Universidades (PID2019-108674RB-100)

Non-melanoma skin cancer (NMSC) is the most common malignancy worldwide, with rising incidence in the recent years. It includes basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Several non-invasive therapies have been developed for its treatment such as topical 5-Fluorouracil (5FU) and photodynamic therapy (PDT), among others. Despite both are appropriated for NMSC treatment, recurrence cases have been reported. To prevent this, in this work we explore the potential of the combination of PDT and 5FU to treat SCC and BCC. First we evaluate the efficacy of PDT in cells resistant to 5FU. For this purpose, we use SCC-13 and CSZ-1 cells, obtained from a human SCC and a murine BCC, respectively. We first induced 5FU resistance in these cell lines by repeated treatments with the drug and then, the efficacy to PDT was evaluated. The results obtained indicated that SCC-5FU resistant cells were sensible to PDT administration, whereas BCC-5FU resistant cells were also resistant to PDT. The observed responses in both cell lines are in concordance to Protoporphyrin IX (PpIX) and reactive oxygen species (ROS) levels produced after the incubation with MAL and subsequent light exposure. The obtained data support the fact that PDT seems to be an appropriate therapeutic option to be administered after 5FU resistance in SCC. However, PDT would not be a choice therapy for resistant BCC cells to 5FU, This research was supported by Spanish grants from Instituto de Salud Carlos III Ministerio de Ciencia e innovacion, ´ and Feder Funds (FIS PI18/00708,PI21/00315 and PI21/00953)