Decoding the immunoregulatory functions of ALKBH5 in the tumor microenvironment

Chunhong Li¹Xiulin Jiang²Yixiao Yuan²Qiang Wang^3*

• ¹Suining Central Hospital, Suining, China
• ²City of Hope, Duarte, United States
• ³Department of Gastroenterology, Suining Central Hospital, Suining, China

N⁶-methyladenosine (m⁶A) modification represents the most prevalent internal RNA modification and plays a pivotal role in regulating RNA metabolism and cellular function. As a major m⁶A demethylase, ALKBH5 not only orchestrates tumor cell proliferation, migration, and metabolic reprogramming but also exerts profound effects on the tumor immune microenvironment (TME). Accumulating evidence has revealed that ALKBH5 regulates immune cell recruitment and function, including CD8⁺ T cells, Tregs, NK cells, and tumor-associated macrophages, by modulating chemokines, cytokines, and metabolic pathways in an m⁶A-dependent or independent manner. Moreover, ALKBH5 influences immune checkpoint expression, such as PD-L1, thereby shaping antitumor immune responses and affecting the efficacy of immunotherapy. Upstream regulatory signals, including hypoxia, inflammation, and epigenetic modifications, further fine-tune ALKBH5 expression and activity. Given its dual roles in promoting or suppressing antitumor immunity depending on tumor type and context, ALKBH5 emerges as both a potential biomarker and therapeutic target. Understanding the multifaceted functions of ALKBH5 in tumor immunity provides new insights into precision immunotherapy and may guide the development of novel combination strategies to overcome resistance.