Abstract
BACKGROUND: Despite remarkable advances in cancer immunotherapy, including immune checkpoint inhibitors and adoptive cell therapies, many patients fail to achieve durable responses due to factors such as immunosuppressive tumor microenvironments, poor tumor antigenicity, and systemic toxicity. These limitations underscore the need for alternative platforms that can elicit robust and localized antitumor immune responses. Bacteria have emerged as promising candidates owing to their natural ability to selectively colonize tumors, stimulate innate and adaptive immunity, and be engineered for therapeutic delivery. However, the therapeutic potential of naturally occurring marine bacterial strains remains largely unexplored in colorectal cancer. METHODS: We screened a panel of marine bacterial strains for antitumor activity in syngeneic and orthotopic mouse models of colorectal cancer. Photobacterium angustum was selected based on its potent antitumor effects. We evaluated tumor colonization, systemic toxicity, and immune responses following intravenous administration. Biosafety was assessed via serum cytokine profiling and hematological analysis. Immune activation was examined by quantitative PCR and immunohistochemistry. RESULTS: P. angustum therapy significantly prolonged survival in tumor-bearing mice and exhibited strong tumor tropism with minimal colonization of healthy tissues. Systemic administration was well tolerated, with low levels of pro-inflammatory cytokines and no hematological toxicity. Treatment enhanced infiltration of T cells, B cells, and neutrophils in the tumor microenvironment, accompanied by elevated intratumoral tumor necrosis factor-α and interferon-γ levels. Additionally, P. angustum demonstrated intrinsic oncolytic activity, contributing to direct tumor cell lysis. CONCLUSIONS: Our findings support P. angustum as a promising platform for bacterial immunotherapy in colorectal cancer, combining tumor-specific colonization, immune activation, and direct tumoricidal effects with an excellent safety profile.