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This complex duality, reminiscent of the balance philosophy pursued by \u201cOnmyoji\u201d 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.<\/jats:p>","DOI":"10.34133\/cancomm.0008","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T20:47:38Z","timestamp":1767905258000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":11,"title":["Tumor Microenvironment Onmyoji: Cytokines with Dual Protumor and Antitumor Roles"],"prefix":"10.34133","volume":"46","author":[{"given":"Yaxuan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Oncology, Zhujiang Hospital, \rSouthern Medical University, Guangzhou 510282, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhujiang Hospital, \rSouthern Medical University, Guangzhou 510282, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaoqu","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, \rChinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xiangya Hospital, \rCentral South University, Changsha 410008, Hunan, China."},{"name":"National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, \rCentral South University, Hunan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhujiang Hospital, \rSouthern Medical University, Guangzhou 510282, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8215-2045","authenticated-orcid":true,"given":"Peng","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhujiang Hospital, \rSouthern Medical University, Guangzhou 510282, Guangdong, China."},{"name":"School of Clinical Medicine, Li Ka Shing Faculty of Medicine, \rThe University of Hong Kong, Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"issue":"1","key":"e_1_3_2_2_2","doi-asserted-by":"crossref","DOI":"10.1186\/s12964-020-0530-4","article-title":"Tumor microenvironment complexity and therapeutic implications at a glance","volume":"18","author":"Baghban R","year":"2020","unstructured":"Baghban R, Roshangar L, Jahanban-Esfahlan R, Seidi K, Ebrahimi-Kalan A, Jaymand M, Kolahian S, Javaheri T, Zare P. 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