Tumor-microenvironment activatable organic photosensitizers for cancer photodynamic therapy

Photodynamic therapy (PDT) represents a clinically approved anticancer modality but suffers from the inherent limitations of nonspecific photosensitizer toxicity to healthy tissues, restricted light penetration depth, oxygen dependency, prolonged photosensitivity, and tumor resistance mechanisms. This review systematically summarizes the rapidly evolving field of tumor microenvironment (TME)-activatable organic photosensitizers, focusing on their rational design principles, cancer treatment applications, and light source selection. These advanced molecular systems exhibit selective activation in response to TME-specific hallmarks such as acidic pH, hypoxia, elevated redox species, and overexpressed enzymes, thereby enabling precise spatiotemporal control of PDT and minimizing off-target side effects. Through comprehensive analysis of representative strategies for engineering stimuli-responsive photosensitizers, the structure-activity relationships and activation mechanisms are highlighted. The selection of light source and light delivery approaches that enhance the performance of organic photosensitizers for PDT is discussed in detail. Finally, current challenges and future directions are critically evaluated, with particular emphasis on their clinical translation potential, to guide advancing smart photosensitizers from bench to bedside and usher in a new era of precision PDT.