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There continues to be a growing acknowledgement of the importance of the tumor microenvironment in responsiveness to most cancer therapies. This chapter provides an overview of our preclinical studies directed at determining the mechanisms of action of photodynamic therapy (PDT), with a focus on its interactions with tumor tissue and with the tumor microenvironment. We review a significant number of molecular pathways activated by PDT. These studies provide convincing evidence that PDT's efficacy can be enhanced by targeted procedures aimed at the prosurvival molecules induced by PDT, as well as by understanding the molecular and cellular mechanisms of PDT within the tumor and its surrounding microenvironment.

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