A study just published in the journal Cell Death Discovery describes for the first time the key role of fatty acid synthase (FASN) in the ability of the immune system to destroy tumors. The research, co-led by Dr. Javier A. Menendez and Dr. Elisabet Cuyàs from the ProCURE program of the Catalan Institute of Oncology in Girona (ICO-Girona)-IDIBGI, shows that disrupting the functioning of this "fat factory" significantly reduces the ability of tumor cells to defend themselves against the body's immune system. FASN inhibition could be explored as a new form of immunotherapy in breast cancer.
FASN: A "shield" for cancer cells
To fuel their rapid growth, cancer cells often rely on a process known as "endogenous lipogenesis," in which they are able to make their own fatty acids. The enzyme FASN plays a critical role in this process, helping tumors survive, spread to other organs and resist treatment. Until now, the role of FASN in protecting tumors from the immune system was not well understood. This new research suggests that FASN not only provides fuel for cancer growth, but also acts as a "defensive shield that allows tumors to evade attack by immune cells, particularly T lymphocytes", the researchers note.
Inhibiting FASN boosts immune response
Bioinformatic analyses carried out in collaboration with the group of Dr. Miguel Ángel Pujana of the ProCURE program at the ICO-L'Hospitalet revealed an increased presence of FASN in tumors of so-called "cold" patients, i.e., those lacking immune activity against cancer cells. To prove the causal relationship between FASN and immune system tolerance, the researchers created cancer cells that lacked the FASN gene using advanced techniques such as CRISPR/Cas9 "genetic scissors". They found that without FASN, these tumor cells were much more susceptible to attack by T cells, our body's natural cancer fighters. In tests mathematically modeled by ICREA Prof. Tomás Alarcón and Dr. Josep Sardanyés of the Centro de Recerca Matemàtica (CRM), cancer cells with low levels of FASN were destroyed much faster and by fewer immune cells. These results show that a previously unknown function of FASN is to protect cancer cells from the "kiss of death," the toxic mechanism triggered when a T lymphocyte comes into contact with a tumor cell, Dr. Menéndez said.
Why is this important for cancer treatment?
Current cancer immunotherapies, such as drugs that target the immune checkpoints PD-1 and PD-L1, help the immune system recognize and attack cancer cells. Many cancers, such as breast cancer, initially fail to respond to these treatments or quickly develop resistance. Dr. Cuyàs points out that "blocking the FASN fat factory is sufficient for breast cancer cells that are highly resistant to immunotherapy to become sensitive to toxic attacks by T lymphocytes. This would support the value of inhibiting FASN as a new way to boost the efficacy of immunotherapy in breast cancer.
A potential therapeutic future is possible: Combining FASN Inhibitors with immunotherapy
How does FASN protect tumor cells from T lymphocytes? How can the role of FASN be exploited as a new form of immunotherapy? The researchers first discovered that FASN affects the way cancer cells manage their energy, particularly in their mitochondria (the cell's power plants). When FASN was removed, mitochondrial function deteriorated, resulting in weaker cancer cells that were more likely to die under immune attack.
FASN also helps cancer cells control PD-L1, a protein that protects tumors from the immune system. PD-L1 sits on the surface of cancer cells and tells T cells to back off, allowing the cancer to grow unchecked. The study showed that without FASN, cancer cells could not maintain PD-L1 on their surface. "FASN produces a 'signaling beacon' that binds to the PD-L1 protein to protect it and guide it on its journey from inside the tumor cell to its surface". This "could open the door to new forms of immunotherapy by combining anti-PD-1/PD-L1 antibodies with FASN inhibitors that would prevent the recycling of the PD-L1 protein from inside the cell", the researchers note.
What Next?
This study shows that FASN, an enzyme responsible for fat production in cancer cells, also plays an important role in helping tumors evade the immune system. Blocking FASN could make cancer cells more vulnerable to the body's natural defenses, increasing the effectiveness of immunotherapies. This discovery holds great promise for developing new cancer treatments and improving outcomes for patients battling immunotherapy-resistant cancers.
Key Points
Reference article: Cuyàs, E., Pedarra, S., Verdura, S. et al. Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity. Cell Death Discov. 10, 417 (2024). https://doi.org/10.1038/s41420-024-02184-z