C.W. Kim, Eon‐Bee Lee
Marine environments harbor immense biodiversity that yields peptides with potent immunomodulatory, antioxidant, and anti-inflammatory activities. These marine-derived immunomodulatory peptides act as molecular mediators of host defense and immune homeostasis across taxa ranging from fish to humans. However, current evaluation approaches, such as two-dimensional cell cultures and animal models, remain insufficient to capture the complex interactions underlying peptide-driven immune regulation. This review integrates recent advances in marine peptide discovery, structural–functional characterization, and elucidation of immunological mechanisms, while critically examining the translational limitations of conventional in vitro and in vivo systems. We highlight organoid technology as a next-generation platform that bridges these gaps through physiologically relevant three-dimensional microenvironments capable of reconstructing innate and adaptive immune responses. Intestinal, hepatic, pulmonary, and skin organoids provide unprecedented opportunities to assess peptide absorption, metabolism, and immunoregulation under near-physiological conditions. Furthermore, the development of fish-derived organoids offers a “fish-to-human” continuum, enabling cross-species validation of conserved pathways within a One Health framework. By integrating marine peptide research with organoid-based immune evaluation, this review proposes a translational roadmap that unites aquatic biomedicine, immunonutrition, and anti-inflammatory drug development. The convergence of organoid-on-a-chip systems, immune-cell co-cultures, and multi-omics analytics is expected to accelerate the preclinical-to-clinical transition of marine peptides, transforming them into functional foods, nutraceuticals, and immunotherapeutics. Collectively, this synthesis delineates how marine peptide–immune–organoid integration advances sustainable biotechnology and precision immunotherapy across species and disciplines.