The role of engineered microbes in immune modulation across cancer, autoimmunity, and infection

Abstract

Engineered microbes are emerging as a new class of living immunotherapeutics. Unlike conventional biologics or cell therapies with fixed mechanisms, these systems can sense and respond to dynamic tissue environments. They integrate environmental, metabolic, and immunological cues and process these signals through programmable biological circuits, executing context-dependent immune modulation with spatial and temporal precision. This review proposes an immune-centered paradigm shift for understanding engineered microbes. We conceptualize them as distributed immune-computational systems composed of sensing, signal processing, memory, and effector modules embedded within host immune networks. Rather than organizing the field by microbial taxonomy or disease category, we focus on immune logic. We describe how engineered microbes detect immune state signals, interpret these inputs through synthetic circuits, and generate outputs that activate, suppress, educate, or reprogram immunity. Applications across cancer, autoimmunity, and infection are discussed with attention to disease-specific immune requirements. We further define immune safety architecture as a core design principle, which includes inflammatory control, tolerance preservation, adaptive regulation, and mechanisms for therapeutic termination. Finally, we outline translational and regulatory considerations, emphasizing immune state-resolved evaluation rather than static pharmacologic endpoints. Together, this paradigm shift positions engineered microbes as programmable immune-modulating systems and provides a conceptual foundation for the rational development of next-generation living immunotherapies.

Keywords

Engineered microbial therapeutics / Living immunotherapies / Immune computation / Systems immunology / Cancer immunomodulation / Immune tolerance engineering / Immune safety architecture / Immune state endpoints

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