Tumor Microenvironment Onmyoji: Cytokines with Dual Protumor and Antitumor Roles

Cytokines are essential components of the tumor microenvironment (TME) and play crucial roles in tumor initiation and progression. As key mediators of interactions between immune cells and tumor cells within the TME, many cytokines exhibit both protumor and antitumor properties. This complex duality, reminiscent of the balance philosophy pursued by "Onmyoji" in traditional Eastern philosophy, which involves observing and regulating opposing forces to achieve harmony, poses marked challenges in translating cytokine therapies from animal studies to clinical applications. More than 20 key cytokines constituting the TME primarily exert their effects through autocrine and paracrine mechanisms: on one hand, they can activate antitumor immune cells, inhibit tumor growth and metastasis, and induce tumor cell apoptosis to exert antitumor effects; on the other hand, they can also recruit abundant immunosuppressive cells, promote angiogenesis, and facilitate the formation of immunosuppressive microenvironments, thereby preventing natural killer and T cells from exerting their cytotoxic antitumor functions. During acute immune responses triggered by tumor antigens, the body typically stimulates dendritic cell maturation and antigen presentation, leading to antitumor immune responses; however, when acute inflammatory reactions are not promptly resolved, they subsequently transform into chronic inflammation, thereby promoting tumor progression and therapeutic resistance, wherein abundant inflammatory cytokines in the TME play crucial roles in this transition. Currently, the major obstacles to cytokine applications in combination immunotherapy are their poor persistence and uncontrolled toxic side effects, resulting in limited therapeutic efficacy; therefore, reducing toxicity while enhancing efficacy has become a top priority in current cytokine therapy-related research. The effectiveness of cytokines exhibits multifactorial regulation influenced by the unique features of the local TME, cytokine concentration, and the responsiveness profiles of target immune effector cells. This review summarizes current research on cytokines with dual protumor and antitumor effects, with a particular focus on the evolution and regulation of their functions during tumor progression, aiming to provide insights for the future development of personalized immunotherapy strategies targeting cytokines.