<p>Cancer remains one of the leading causes of morbidity and mortality worldwide, and its treatment is often compromised by tumor hypoxia, a condition associated with poor therapeutic outcomes. Hypoxia is particularly detrimental to oxygen-dependent therapies such as photodynamic therapy (PDT), which relies on the generation of reactive oxygen species and singlet oxygen to induce cancer cell death. Recently, biocompatible oxygen-generating systems, including photosynthetic microalgae, have emerged as promising alternatives capable of locally and continuously increasing oxygen levels under light exposure. In this context, this study investigates the impact of microalgae-mediated oxygen production on the chorioallantoic membrane (CAM) vascular network and its potential to enhance PDT efficacy. Recognizing the critical role of oxygen in PDT efficacy, we investigated whether <i>Chlamydomonas reinhardtii</i>, a photosynthetic microalga, could enhance treatment outcomes, using the CAM assay. Using methylene blue (MB) as the photosensitizer, three experimental groups were analyzed to assess vascular changes at a specific embryonic developmental day. PDT alone reduced vascular ramification by approximately 50%, whereas treatment with illuminated microalgae alone promoted an approximately 20% increase in vessel growth, indicating a pro-angiogenic effect. In contrast, the combination of PDT with oxygen-releasing microalgae produced a synergistic response. Specifically, the combined treatment using a reduced MB concentration achieved a ~ 50% reduction in vascularization, comparable to PDT alone but with a tenfold lower photosensitizer dose, corresponding to an order-of-magnitude increase in treatment efficiency. These findings suggest that microalgae-mediated oxygenation can significantly enhance PDT and support further exploration in mammalian in vivo models.</p>