Antimicrobial photodynamic therapy (aPDT) operates through the light-activated excitation of photosensitizers, generating reactive oxygen species that simultaneously damage multiple essential microbial structures. This broad-spectrum, multi-target mechanism holds strong promise for combating antimicrobial-resistant microorganisms. Beyond these direct effects, other biological events can occur, potentially influencing microbial physiology, host responses, or overall treatment efficacy. These intermediate processes can yield beneficial outcomes or unintended consequences, highlighting the need for closer examination and careful monitoring. We conducted a comprehensive literature review of studies published over the past 25 years that investigated microbial survival mechanisms, modulation of virulence genes, host immune responses, microbiota interactions, and any evidence of cross-resistance following aPDT treatments. Antimicrobial photodynamic therapy remains at the forefront of alternative antimicrobial strategies, supported by extensive evidence demonstrating its broad-spectrum efficacy and its low propensity to select for resistance under standard conditions. Conversely, a growing body of evidence highlights the possible complex effects of aPDT. Under repeated or sublethal exposure, microbes can marshal adaptive responses that, in still rare cases, may confer tolerance, classical resistance, or even heightened virulence. aPDT can also modulate host–microbe interactions, immune signaling, or the activity of other antimicrobials. These findings point to both the therapeutic benefits of aPDT but also potential side effects associated with its improper use. Although aPDT currently exhibits minimal resistance development, it should not be considered inherently “resistance-proof.” Continued research, rigorous monitoring, the use of physiologically relevant models, and optimized dosing and light-delivery protocols are essential to safeguard aPDT’s long-term therapeutic potential. Antimicrobial photodynamic therapy (aPDT) can act not only on microbial pathogens, but also on host cells and components of the immune system. This review synthesizes the current literature on the direct and indirect outcomes of aPDT, highlighting its therapeutic potential alongside potential unintended or deleterious effects. Key aspects include possible microbial adaptation and resistance development, modulation of pathogen virulence, immunological responses, impact on the host microbiota, and interactions with other antimicrobial agents. A comprehensive understanding of these mechanisms is crucial for refining the experimental and clinical use of photodynamic therapy. (Figure created with BioRender.com). • aPDT can display multiple benefits yet may also carry potential side effects. • aPDT should not be assumed to be inherently “resistance‑proof”. • Microorganisms may develop adaptations that might lessen aPDT’s long‑term efficacy. • A deeper understanding of microbial adaptation to aPDT is needed. • Precise, well‑controlled application of aPDT remains essential.
Bonnardot et al. (Sun,) studied this question.