Cancer Immunotherapy Enhanced by Rewiring T-Cell Metabolism

Solid tumors create a hostile environment that challenges the effectiveness of T cells – key players in our immune system’s defense against cancer. Researchers from the VIB-KU Leuven Center for Cancer Biology, in collaboration with other scientists, have discovered a way to enhance the immune system's ability to fight cancer by reprogramming T-cell metabolism.

Their study, published in Nature Metabolism, reveals how metabolic reprogramming can boost T-cell survival and efficacy in the tumor microenvironment.

Harnessing the immune system to combat cancer

The immune system – composed of lymph nodes, the spleen and various immune cells – plays a crucial role in protecting the body from infections and diseases, including cancer. Under normal circumstances, the immune system detects and eliminates faulty cells before they can develop into tumors. However, cancer can evade immune surveillance by suppressing immune responses, disguising itself, or creating an environment that weakens immune cells.

Immunotherapies – such as checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies – have been developed to enhance the immune system’s ability to recognize and destroy tumors. Despite their success in treating some cancers, these therapies often struggle against solid tumors due to the tumor microenvironment’s low oxygen levels, nutrient deprivation and immunosuppressive signals that inhibit T-cell function.

“Solid tumors are very complex in their composition, with many types of cells interacting with each other (e.g., cancer cells, stromal cells and immune cells),” Dr. Samantha Pretto, a post-doctoral researcher at VIB-KU Leuven Center for Cancer Biology, told Technology Networks. “Cancer cells can directly impact the effect of immunotherapies through immune escape mechanisms, such as the expression of immune checkpoint molecules and release of waste products. They can also favor an immunosuppressive environment by recruiting and sustaining anti-inflammatory immune cells,” she continued.

The researchers explored whether reprogramming T-cell metabolism – allowing them to utilize alternative energy sources – could help T cells thrive in these hostile conditions, improving their cancer-fighting abilities.

“Over recent years immunometabolism has become a hot topic in research,” said Dr. Massimiliano (Max) Mazzone, professor at VIB-KU Leuven Center for Cancer Biology.

“Here we modulate the metabolism of the T cells, to support their endurance once re-infused in the body. This could be a complementary approach to CAR T-cell therapies or in general adoptive T-cell transfer approaches,” said Pretto.

Targeting T-cell metabolism to improve immunotherapy

To uncover metabolic factors that influence T-cell functionality, Mazzone and the team performed an in vivo CD8⁺ T-cell CRISPR screen across primary tumors, metastatic sites and lymphoid organs. Using single-cell RNA sequencing, they identified key metabolic determinants that enhance T-cell responsiveness to anti-PD-1 checkpoint blockade therapy, a common immunotherapy used against solid tumors.

Their analysis highlighted a critical role of Elongation of Very Long-chain fatty acids protein 1 (Elovl1), which encodes an enzyme involved in the synthesis of saturated very long-chain fatty acids. Inhibiting Elovl1 prompted T cells to shift their energy metabolism from glucose dependence to fatty acid oxidation, enabling them to sustain their function in the nutrient-scarce tumor microenvironment.

“The targeting of Elovl1 sustained effector functions and memory phenotypes in CD8⁺ T cells,” Mazzone said. “Mechanistically, the accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T-cell receptor signaling,” he added.

In mouse models of pancreatic ductal adenocarcinoma and melanoma, Elovl1 inhibition significantly enhanced T-cell anti-tumor activity, particularly when combined with anti-PD-1 therapy. This metabolic reprogramming not only boosted the survival of T cells but also amplified their ability to attack cancer cells.

“Elovl1-deficient T cells present increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumor microenvironment. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with αPD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumors,” Mazzone highlighted.

The findings suggest that modulating T-cell metabolism could enhance the effectiveness of existing immunotherapies, offering new hope for patients with treatment-resistant cancers.

Challenges remain before viable cancer treatments can be developed

This research underscores the potential of metabolic engineering in immunotherapy, paving the way for innovative strategies to overcome the challenges posed by solid tumors. However, hurdles still need to be overcome to create a viable cancer treatment.

“Metabolic manipulation is something that is just starting to be pursued in pharmaceutical companies. We don’t know how long this metabolic intervention would last once the cells are re-infused and if this metabolic alteration could lead to side effects,” said Pretto.

Mazzone and the team hope to build on their findings to potentiate anti-tumoral activity through immunometabolism research.

“It would be interesting to analyze the different types of T cells or general immune cells infiltrating the tumor and see which metabolic pathways are enhanced in both the effective anti-tumoral immune cells and exhausted/pro-tumoral immune cells,” said Mazzone. “These would help us understand the metabolic pathways/enzymes sustaining diverse immune cell phenotypes in pancreatic cancer or other solid tumors.”

“The other side of the coin that we are exploring is the epigenetic and metabolic rewiring of the myeloid cell compartment to block immunosuppression and elicit non-antigenic anti-tumor responses,” he concluded.

Reference: Pretto S, Yu Q, Bourdely P, et al. A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours. Nat Metab. 2025:1-23. doi: 10.1038/s42255-025-01233-w

About the interviewees

Credit: @VIB.

Dr. Samantha Pretto was born in Vimercate, a city close to Milan, in the north of Italy. Interested in science since she was young, she obtained a bachelor's and a master's in medical biotechnology, specializing in oncology, at the University of Milan. Fascinated by the interaction between cancer and immune cells, she joined the lab of Professor Max Mazzone for her PhD on T-cell metabolism in the context of cancer.

Dr. Massimiliano (Max) Mazzone graduated in medical biotechnology at the Medical School of the University of Torino, Italy, and then performed his PhD in cell science and technologies at the Institute for Cancer Research of Torino, under the supervision of Professor Comoglio. In November 2006, he moved to Belgium as an EMBO-awarded postdoctoral fellow in the lab of Professor Peter Carmeliet, at the University of Leuven, Belgium. Since October 2009, he has been heading the Lab of Tumor Inflammation and Angiogenesis, at the Center for Cancer Biology, part of VIB in Leuven, and, since 2017, he has been a full professor at the University of Leuven. In 2024, he was also appointed as a professor at Humanitas University in Milano.