In complex organisms, functional units must interact cohesively to maintain homeostasis, especially within mucosal barriers that house diverse, specialized cell exposed to constant environmental challenges. Understanding how homeostasis at mucosal barriers is maintained and how its disruption can lead to autoimmune diseases or cancer, requires a holistic view. Although omics approaches and systems immunology have become powerful tools, they are not without limitations
interpretations may reflect researchers' assumptions, even if other explanations exist. In this perspective, I propose that applying game theory concepts to mucosal immunology could help interpret complex data, offering fresh perspectives and supporting the exploration of alternative scenarios. By framing the mucosal immune system as a network of strategic interactions with multiple possible outcomes, game theory, which analyzes strategic interactions and decision-making processes, could illuminate novel cell types and functions, cell interactions, and responses to pathogens and commensals, leading to a more comprehensive understanding of immune homeostasis and diseases. In addition, game theory might encourage researchers to consider a broader range of possibilities, reduce the risk of myopic thinking, and ultimately enable a more refined and comprehensive understanding of the complexity of the immune system at mucosal barriers. This perspective aims to introduce game theory as a complementary framework for mucosal immunologists, encouraging them to incorporate these concepts into data interpretation and system modeling.