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Photodynamic therapy (PDT) is a reactive oxygen species (ROS)-dependent treatment modality which has emerged as an alternative cancer therapy strategy. However, in solid tumors, the therapeutic efficacy of PDT is strongly reduced by hypoxia, a typical feature of many such tumors. The tumor-associated carbonic anhydrases IX (hCA IX) and XII (hCA XII), which are overexpressed under hypoxia are attractive, validated anticancer drug targets in solid tumors. Current challenges in therapeutic design of effective PDT systems aim to overcome the limitation of hypoxia by developing synergistic CA-targeted therapies combining photosensitizers and hCA IX/XII inhibitors. In this review, the current literature on the use of hCA IX/XII inhibitors (CAi) for targeting photosensitizing chemical systems useful for PDT against hypoxic solid tumors is summarized, along with recent progress, challenges, and future prospects. hCA IX/XII-focused photosensitizers have recently provided new generation of compounds of considerable potential. Proof of concept of  in vivo  efficacy studies suggested enhanced efficacy for CAi-PDT hybrid systems. Further research is needed to deepen our understanding of how hCA IX/hCA XII inhibition can enhance PDT and for obtaining more effective such derivatives.

Are tumour-associated carbonic anhydrases genuine therapeutic targets for photodynamic therapy?