ABSTRACT The immune microenvironment includes immune cells, cytokines, extracellular matrix, vesicles, etc. The interactions between these components form a unique local immune microecology. Although immunity serves as the defense against external pathogens, aberrant immune activation often contributes to disease development. Chronic diseases, a broad category of noncommunicable conditions characterized by long latency and prolonged course, are increasingly recognized for their intricate relationship with the immune microenvironment. Herein, we comprehensively summarize how the immune microenvironment, through its complex regulatory network, influences the progression and manifestation of chronic diseases. We further explore the potential of targeting the immune microenvironment as a therapeutic strategy, aiming to provide new insights and directions for the prevention, diagnosis, and treatment of chronic diseases.