Bioinspired Photosynthetic Bacterial Dormancy Modulates Gut Microbiota to Potentiate Colorectal Cancer Immunotherapy

ABSTRACT Gut microbiota dysbiosis critically limits the efficacy of immunotherapy in colorectal cancer (CRC), motivating the use of oral probiotics as a safe and noninvasive intervention. However, conventional probiotic strategies predominantly rely on gut‐derived commensal bacteria and are constrained by poor gastrointestinal stability, limited intestinal colonization, and strong host‐specific microbial contexts, resulting in inconsistent therapeutic outcomes. Here, we present a biomimetic oral bacterial platform that addresses these intrinsic limitations by programming non–gut‐derived photosynthetic bacteria (PSB) into a reversible dormant state. PSB are encapsulated with a pH‐responsive methacrylic acid–ethyl acrylate copolymer to form a spore‐like formulation (PSB@L), which protects bacterial viability during gastric transit and specific reactivation in the intestine. PSB exploit their metabolic flexibility to occupy distinct ecological niches with minimal competition with resident commensals, selectively enriching beneficial microbiota while suppressing tumor‐promoting bacteria, thereby restoring intestinal microecological balance. Simultaneously, activated PSB stimulate intestinal innate immune responses and enhance dendritic cell–mediated antigen presentation, reinforcing antitumor immunity. By integrating controlled bacterial dormancy with function‐oriented microbiota remodeling and immune activation, PSB@L markedly enhances immunotherapeutic efficacy against CRC. This work demonstrates that effective microbiota‐assisted immunotherapy can be achieved without reliance on gut‐derived or host‐matched probiotics, establishing a robust alternative paradigm for oral microbial cancer immunotherapy.