Acetate Supplementation Shows Promise in Overcoming Cancer Therapy Resistance

Updated‍ June 21, 2025
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A new ⁣study from the University of Alabama at Birmingham (UAB) suggests a potential strategy to improve the effectiveness of cancer immunotherapy. Researchers found that acetate supplementation can overcome resistance to⁣ immune checkpoint blockade (ICB) therapy,a treatment that has revolutionized care for advanced cancers but often⁤ sees its impact limited by⁢ therapeutic resistance.

The research, led⁣ by dr. Lewis Zhichang Shi, focused on tumor-infiltrating lymphocytes (TILs), immune cells that can kill tumor cells. The challenge is that the cancer microenvironment,⁣ often low in oxygen due to rapid tumor growth, can render these TILs ineffective.The study, published in Nature Communications, explored how to rejuvenate these anti-cancer TILs in such conditions.

Shi and his team discovered that HIF1α in T cells is crucial for the induction of interferon gamma (IFN-γ) in low-oxygen environments. IFN-γ is a cytokine known to boost the tumor-killing capacity of T cells.The⁣ researchers also noted that glycolysis, an ⁢alternative metabolic process that produces energy without oxygen, is required for IFN-γ induction in T cells.

The UAB team demonstrated that HIF1α-glycolysis ⁢is essential for IFN-γ induction in oxygen-deprived T cells.They used mouse models, metabolic flux analysis, and pharmacological approaches to show HIF1α’s key⁣ role in⁤ responding to hypoxia.

Experiments showed that deleting HIF1α from T cells prevented the metabolic shift needed for IFN-γ induction and suppressed IFN-γ ⁤production. Conversely, stabilizing HIF1α increased IFN-γ ⁣under hypoxic conditions. ⁢Hypoxic ⁢T cells lacking HIF1α were also less effective at killing tumor⁢ cells in vitro,and mice with HIF1α-deleted T ⁤cells did not respond to ICB therapy.

Further investigation revealed that the loss of ⁣HIF1α diminished glycolytic activity, leading⁢ to depleted intracellular acetyl-CoA and reduced activation-induced cell death (AICD). Supplementing growth media ⁤with⁣ acetate restored acetyl-CoA, re-engaged AICD, and rescued IFN-γ production.

In living mice, acetate supplementation proved effective in bypassing ICB resistance. Mice with HIF1α-deletion that received acetate followed by combination ICB therapy showed significant tumor suppression and reduced ‍tumor weights.

“TILs and tumor cells utilize the same metabolic pathways for their growth and function, and co-live in⁣ the metabolically harsh tumor-microenvironments characterized by hypoxia and poor⁤ nutrition, placing⁤ them in a fierce metabolic tug-of-war,” Shi said. “How to tilt this metabolic battle to favor TILs ⁤would be key, and we showed⁢ that acetate supplementation restored IFN-γ ⁣production in Hif1α-deletion-TILs and overcame ICB resistance derived ⁣from⁢ HIF1α loss in T cells.”

What’s next

The study suggests that impaired HIF1α function in T cells is a major mechanism of therapeutic resistance to ICBs. Acetate supplementation may offer a new avenue to improve cancer therapy outcomes by restoring IFN-γ production and overcoming ICB resistance.