image: Cytokines contribute to the antitumor response through several key pathways and interactions with different immune cells. These include the following: (a) Natural killer (NK) cells: Cytokines such as IFN-γ, IL-12, and IL-15 activate NK cells. Activated NK cells then release perforin and granzyme, which induce apoptosis in tumor cells. (b) Natural killer T (NKT) cells: These cells also release perforin in response to cytokines, contributing to the direct killing of tumor cells. (c) γδ T cells: Similar to NK and NKT cells, γδ T cells release perforin and granzyme to target and kill tumor cells. (d) Immature dendritic cells: Cytokines activate immature dendritic cells, which then mature and present tumor-associated antigens (TAAs) to other immune cells, enhancing the adaptive immune response. (e) Mature dendritic cells: These cells facilitate the activation of B cells, CD8+ T cells, and CD4+ T cells through antigen presentation. This activation leads to antibody-dependent cellular cytotoxicity (ADCC), cytotoxic effects, and a Th1 response, all of which contribute to the antitumor immune response. (f) M1 tumor-associated macrophages (M1-TAMs): Cytokines like IFN-γ and IL-1 activate M1-TAMs, which then engage in phagocytosis of tumor cells and secrete factors that promote inflammation and further immune activation. (g) Neutrophils (N1-TANs): These cells, activated by IL-8 and other cytokines, also participate in phagocytosis and contribute to the destruction of tumor cells. Overall, cytokines orchestrate a multifaceted immune response involving various cell types, enhancing both the innate and adaptive immune systems’ ability to target and eliminate tumor cells. Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; CD4+ T cell, CD4-positive T cell; CD8+ T cell, CD8-positive T cell; DCs, dendritic cells; IFN-γ, interferon gamma; IL-1, interleukin-1; IL-8, interleukin-8; IL-12, interleukin-12; IL-15, interleukin-15; M1-TAMs, M1 tumor-associated macrophages; N1-TANs, N1 tumor-associated neutrophils; NK cells, natural killer cells; NKT cells, natural killer T cells; TAAs, tumor-associated antigens; Th1, T helper 1; γδ T cells, gamma delta T cells.
Credit: Yaxuan Wang, Anqi Lin, Zaoqu Liu, Quan Cheng, Jian Zhang, and Peng Luo
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.
Journal
Cancer Communications
Method of Research
Literature review
Subject of Research
Cells
Article Title
Tumor Microenvironment Onmyoji: Cytokines with Dual Protumor and Antitumor Roles
Article Publication Date
28-Jan-2026
COI Statement
The authors declare that they have no competing interests.