Microbial Photosynthetic Oxygenation and Radiotherapeutic Sensitization Enables Pyroptosis Induction for Combinatorial Cancer Therapy

Abstract Rectal cancer surgery is challenging due to the complex anatomy, making it difficult to achieve clear surgical margins. Radiotherapy (RT) plays a crucial role, especially in treating locally recurrent rectal cancer and preserving anal function. However, its effectiveness is often limited by tumor hypoxia, particularly prevalent in hypoxic regions near the bowel wall in colorectal cancer. Hypoxia contributes to both radiation resistance and apoptosis resistance, compromising RT outcomes. To overcome hypoxia‐driven radiotherapy resistance, this work designs and engineers a radiotherapy‐sensitizing bioplatform for efficient cancer RT. It combines lanthanum oxide nanoparticles (La 2 O 3 NPs) with cyanobacteria, which produces oxygen through photosynthesis. This bioplatform uniquely reduces tumor hypoxia, enhances radiation deposition, and improves RT efficacy. La 2 O 3 NPs further enhance reactive oxygen species (ROS) production induced by radiation, triggering pyroptosis via the ROS‐NLRP3‐GSDMD pathway, while RT amplifies pyroptosis through GSDME, circumventing tumor apoptosis resistance. The further integrated thermosensitive hydrogels ensure precise localization of the bioplatform, reducing systemic toxicity and improving therapeutic specificity. Compared to conventional therapies, this dual‐action system addresses hypoxia, RT resistance, and apoptosis resistance more effectively. In vivo and in vitro hypoxia models validate its potent anti‐tumor efficacy, offering valuable insights for refining clinical treatment paradigms.