Illuminating the path to oncolysis: rise of microbial phototherapy

Phototherapy, which includes photothermal therapy (PTT) and photodynamic therapy (PDT), has attracted significant interest in the field of cancer treatment due to its spatiotemporal controllability and minimal invasiveness. Nonetheless, the utilization of phototherapy as a standalone treatment faces several formidable challenges. These encompass the non-specific distribution and rapid clearance of phototherapeutic agents, leading to inadequate antitumor efficacy and potential systemic toxicity. Additionally, the hypoxic and immunosuppressive nature of the tumor microenvironment (TME) substantially impairs therapeutic outcomes. In response, natural and engineered microorganisms, such as bacteria, viruses, and microalgae, have been developed as innovative platforms to enhance traditional phototherapy. By exploiting their tumor-targeting capacities, these microorganisms facilitate the precise delivery and localized expression of phototherapeutic agents within tumors, thus ensuring high intratumoral accumulation, reduced systemic exposure, and improved stability. The inherent characteristics of these microorganisms, including direct oncolysis, activation of antitumor immune responses, metabolic modulation, and oxygen production, enable them not only to mediate tumor destruction but also to remodel the TME. This review examines the advantages of incorporating microorganisms into phototherapy and offers a critical, comparative analysis of various microbial platforms to clarify their unique targeting behaviors, safety profiles, and therapeutic functions. It also outlines recent advancements in microbial phototherapy strategies, encompassing single-mode PTT/PDT, multimodal synergistic therapies, and imaging-guided therapies. Finally, the review addresses foreseeable challenges and prospects, aiming to provide direction for future research and clinical translation.