Short-chain fatty acids regulate cytokine programs in tumor immunity: mechanisms and translational opportunities

Qi Song^1,2,3, Ming Li^1,2, Zhiliang Jin⁴, Han Zhang^1,2, Haisen Yin^1,2,*, Shiyun Tan^1,*, Baoping Yu^1,*
1 Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
2 Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, China
3 Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
4 Department of Oncology, The Second Clinical Medical College, Yangtze University, Jingzhou, China
* Corresponding Author: Haisen Yin. Email: email ; Shiyun Tan. Email: email ; Baoping Yu. Email: email
(This article belongs to the Special Issue: Inflammation in Disease: When Cytokine Conversations Tell the Whole Story)

European Cytokine Network https://doi.org/10.32604/ecn.2026.084574

Received 25 April 2026; Accepted 05 June 2026; Published online 29 June 2026

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Abstract

Short-chain fatty acids (SCFAs) are increasingly recognized as active modulators of tumor immunity. However, organizing evidence only by tumor type, metabolite species, or individual pathway may not fully explain their context-dependent effects. This Review clarifies how SCFAs regulate tumor immunity by remodeling cytokine and chemokine networks within the tumor microenvironment and defines the contextual factors that determine whether these effects support or restrain antitumor responses. We organize SCFA-driven effects into four functional cytokine domains: pro-inflammatory, antitumor effector, immunosuppressive, and chemotactic/angiogenic mediators. Across these domains, SCFAs act through inflammasome modulation, receptor-mediated signaling, epigenetic regulation, and metabolic reprogramming. We propose that the translational potential of SCFAs depends on context-aware application, given that their immunological effects are shaped by SCFA subtype, exposure compartment, dose, tumor stage, cellular lineage, tissue environment, and therapeutic context. Importantly, current mechanistic insights remain largely butyrate-based, with limited evidence for other SCFAs or clinically relevant exposure settings. We further discuss the implications of these patterns for immune checkpoint blockade, cell- and virus-based therapies, radiotherapy, and chemotherapy. Overall, SCFA-mediated modulation of cytokine networks provides a useful framework for understanding metabolic regulation of tumor immunity and its translational potential.